COMPOUNDS USEFUL IN THE TREATMENT OF NEUROFIBROMATOSIS

Abstract: The present invention relates to compositions useful in the treatment of benign proliferative disorder neurofibromatosis comprising a farnesyl protein transferase inhibitor. Further contained in this invention are methods of treating benign proliferative disorder neurofibromatosis in a mammal, which methods comprise administering to said mammal, a farnesyl proteine transferase inhibitor.

Description: TITLE OF THE INVENTION COMPOUNDS USEFUL IN THE TREATMENT OF NEUROF1BROMATOSIS BACKGROUND OF THE INVENTION A genetic defect underlies von Recklinghausen neurofibromatosis, known as type 1 neurofibromatosis (NFl), which is inherited as an autosomal dominant trait, and affects 1 in 3,500 humans. Analysis of the steps that lead to disease manifestations and development of therapeutic strategies against NFl is complicated by the number of abnormalities in NFl patients and the diversity of cell types involved. A National Institute of Health consensus panel has defined diagnostic criteria, two or more of which define a diagnosis of NFl . The criteria are: 1) six or more cafe-au-lait macules over 5mm in greatest diameter (prepubertal) or over 15mm (postpubertal); 2) freckling in the axillary or inguinal regions; 3) optic glioma; 4) two or more iris Lisch nodules; 5) a distinct osseus lesion; 6) a first degree relative with NFl; and 7) two or more nerve sheath tumors (neurofibromas) of any type or one plexiform neurofibroma. More recently it has become clear that up to 40% of children with NFl show learning disabilities. The NFl gene is located on the proximal long arm of human chromosome 17, and extends about 320kb of genomic DNA; all informative NFl families showed linkage to this locus. Mutational analysis identified mutations in about 15% of patient DNA with no identified hot spots; remaining mutations may be in untested intron sequences. Mutations including translocations, insertions, deletions and base-pair substitutions predict truncated or inactive protein, with no evidence for dominant negative effects. In malignant tumors (neurofibrosarcomas, pheochromocytomas and juvenile myelocytic leukemias) associated with NFl, mutations in the previously normal somatic allele have been detected, suggesting that the NFl gene can be categorized with tumor suppresser genes such a Rb and NF2. However, it remains unclear if mutations in both NFl alleles is a prerequisite for the formation of benign lesions, including neurofibromas. Ras is an intracellular messenger activated by binding GTP subsequent to receptor activation; Ras activation recruits the serine- threonine kinase raf to the plasma membrane and leads to activation of raf by an unknown mechanism. Raf activation leads to activation of a cascade of protein kinases (ERKs and MAPKs) and changes in gene transcription. Other pathways are also downstream of ras activation. In many tumor cells, mutant oncogenic alleles of ras genes specify structurally altered forms of Ras which have a reduced ability to hydrolyze GTP when compared with the wild type ras gene product (Gibbs et al.. Proc. Natl. Acad. Sci. USA. 81:5704-5708 (1984); McGrath et al., Nature. 310:644-649 (1984); Sweet et al-, Nature 311:273-275 (1984)). Additionally, these oncogenic forms of Ras have been found to exhibit a greatly diminished sensitivity to the ras GTPase activating protein (GAP) (Trahey and McCormick, Science, 242:1697-1700 (1987); Vogel et al., Nature. 335:90-03 (1988)). These findings suggest that the GTP-bound state of Ras represents an activated, signal-emitting form of Ras which is normally inactivated through GTP hydrolysis, yielding an inactive GDP-bound form of the protein. Because of their reduced intrinsic GTPase activity and resistance to GAP, oncogenic forms of Ras may be trapped in this activated state for extended periods of time, thereby flooding the cell with growth-stimulatory signals. In part because Ras has no other apparent catalytic activities associated with it, it is hypothesized that Ras acts as a regulatory subunit of another protein that serves as its effector, releasing mitogenic signals when prompted to do so by activated, GTP-bound Ras. One candidate for such an effector protein is GAP itself. However, GAP has no obvious catalytic domains that might play a role in metabolic processes associated with cell proliferation. For this reason, GAP itself might act as a signal transducer which passes Ras-initiated signals on to bona fide effectors still further downstream in the signaling cascade. The NFl mRNA is >12kb in size, and encodes a 320kd protein, neurofibromin. A 360 amino acid segment near the middle of the protein sequence shows 30% homology to the catalytic domain of the GTPase activating protein (GAP) and the yeast IRAl and IRA2 proteins that stimulate GTPase activity of Ras proteins. The GAP-related domain of neurofibromin exhibits GAP activity toward human and yeast Ras proteins and complements the loss of function in yeast IRA mutants. Numerous studies have confirmed the GAP activity of full-length neurofibromin as well as the GAP-related domain. Loss of neurofibromin through mutations at the NFl locus are predicted to cause a failure to terminate Ras signals, and to cause alterations in growth and differentiation of affected cells. It has been shown that neurofibrosarcoma (malignant Schwann cell) cell lines contain little neurofibromin, and at the same time show increased levels of GTP bound to Ras , suggesting a correlation between loss of neurofibromin and Ras regulation in such cells (deClue et al., Cell, 69:265-273 (1992)). These data suggest that neurofibromin is the major regulator of Ras in malignant Schwann cells, in spite of the fact that these cells contain normal levels of pl20GAP protein. Decreasing levels of Ras-GTP in the neurofibrosarcoma cells by overexpressing pl20GAP led to reduced frequency of colony formation and decreased growth in agar, suggesting that Ras-GTP contributes to some of the transformed properties of these malignant Schwann cells. Recently mice containing targeted inactivating mutations at the NFl locus were studied (Brannan et al., Genes and Dev., 8:1019-1029 (1994)). Neurofibromin expression in adult mice and embryos from transgenic mice that were heterozygous or homozygous at the NFl locus was analyzed. Neurofibromin was found to be present at roughly 50% of normal levels in heterozygous mice and was undetectable in homozygous mice, indicating that the latter were true nulls. Null embryos die between day 11.5 and 14 of gestation, prior to significant nerve development, apparently as a result of cardiac malformation. Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al, Science, 260:1934-1937 (1993) and G.L. James et al, Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras- dependent tumors in nude mice (N.E. Kohl et al, Proc. Natl. Acad. Sci U.S.A., 97:9141-9145 (1994) . Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al, ibid; Casey et al, ibid; Schafer et al, Science 245:319 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol Chem., 265:14701-14704 (1990); Schafer et al, Science, 249: 1133-1139 (1990); Manne et al, Proc. Natl. Acad. Sci USA, 57:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis. Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are competitive with farnesyl diphosphate (FPP) and can be structural analogs of FPP or not directly analogous. The second class of inhibitors are competitive with the protein substrates (e.g., Ras) for the enzyme. The protein substrate- competitive inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al, ibid; Reiss et. al, ibid; Reiss et al, PNAS, 88:132-136 (1991)). Such compounds may inhibit protein 1 prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al, Science, 260:1934-1931 5 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). Recently, protein substrate-competitive inhibitors that lack a thiol moiety have been described (WO 95/09000; WO 95/09001; WO 95/10514; WO 95/10515; WO 95/10516; WO 95/08542; WO 95/11917; and WO 95/12612). Inhibitors of FPTase have recently been described that 10 incorporate characteristics of both farnesyl pyrophosphate and the CAAX motif (R.S. Bhide et al., Bioorg. Med. Chem. Lett., 4:2107-2112 (1994) and (V. Manne et al., Oncogene, 10:1763-1779 (1995)). It is, therefore, an object of this invention to develop methods of treating and preventing benign proliferative disorder 15 neurofibromatosis which utilize compounds which are known to be inhibitors of farnesyl-protein transferase. SUMMARY OF THE INVENTION 20 The present invention relates to compositions useful in the prevention and treatment of benign proliferative disorder neurofibromatosis comprising a farnesyl protein transferase inhibitor. Further contained in this invention are methods of treating and preventing benign proliferative disorder neurofibromatosis in a mammal, which 25 methods comprise administering to said mammal, a farnesyl protein transferase inhibitor. BRIEF DESCRIPTION OF THE FIGURES * -, 30 FIGURE 1: Effect of a Farnesyl-protein Transferase Inhibitor on NFl Schwann Cells: • Cell proliferation of NFl wild type mouse Schwann cells (+/+) and mutant type cells (-/-) which were preincubated with various concentrations Compound A. After preincubation the cells were exposed to medium containing glial growth factor. FIGURE 2: Proliferation of NFl Null Schwann Cells in the Presence of Forskolin : Effects of exposure of NFl wild type mouse Schwann cells (+/+) and mutant type cells (-/-) to media containing various concentrations of forskolin is shown. FIGURE 3: Effect of a Farnesyl-protein Transferase Inhibitor on Forskolin mediated Proliferation: Effects of preincubation of NFl mutant (-/-) type Schwann cells with Compound A is shown. Cell proliferation was mediated by the addition of forskolin. DETAILED DESCRIPTION OF THE INVENTION According to one aspect of this invention, it is now possible to achieve a therapeutic effect in a mammal in need of treatment of benign proliferative disorder neurofibromatosis with pharmaceutically effective amounts of a farnesyl protein transferase inhibitor. Such a compound is also useful in the prevention of the disease. It has been discovered that Schwann cells lacking neurofibromin proliferate more slowly than do wild type Schwann cells in response to axons or glial growth factor (GGF), specific Schwann cell mitogens. Those null Schwann cells also show increased levels of GTP bound to Ras and show hyperplasia in response to forskolin, an activator of adenylate cyclase, that may mimic endogenous factors in Schwann cell tumors in NFl patients. It has been surprisingly discovered that a farnesyl-protein transferase inhibitor inhibits the forskolin-mediated proliferation of null Schwann cells. Such inhibition of that proliferative effect is useful in the treatment of NFl associated with mutations in the NFl gene that leads to loss or reduction of neurofibromin activity. - 1 - The present invention is not limited in any way by the specific farnesyl-protein transferase inhibitor. Either a protein substrate- competitive inhibitor and/or a farnesyl pyrophosphate-competitive inhibitor now known or subsequently discovered or developed may be utilized. Farnesyl-protein transferase inhibitors useful in the instant invention are described hereinbelow. The composition of the instant invention may comprise a protein substrate-competitive farnesyl-protein transferase inhibitor that incorporates a cysteinyl or sulfhydryl containing moiety at the N- terminus of the molecule. Thus the following compounds, well known in the art, are useful as protein substrate-competitive inhibitors in the instant invention: a) a peptide that comprises the amino acids CAl A2X, wherein: C = cysteine; Al = an aliphatic amino acid; A2 = an aliphatic amino acid; and X = any amino acid; b) Cys - Xaal - Xaa2 - Xaa3 - NRR 1 , wherein Cys = cysteine; Xaal = any amino acid in the natural L-isomer form; Xaa^ = any amino acid in the natural L-isomer form; and Xaa3 - NRR! = an amide of any amino acid in the natural L- isomer form, wherein R and R! are independently selected from hydrogen, Cl-Cl2 alkyl, aralkyl, or unsubstituted or substituted aryl; c) Cys - Xaal _ χ aa 2 _ Xaa3 , wherein Cys = cysteine; Xaal — an y amino acid; Xaa^ = the amino acid phenyl alanine or a p- fluorophenylalanine; and Xaa^ = any amino acid; d) Cys - Xaal - dXaa^ - Xaa3, wherein Cys = cysteine; Xaal = an y amino acid in the natural L-isomer form; dXaa^ = any amino acid in the natural L-isomer form; and Xaa3 = any amino acid in the natural L-isomer form; e) U.S. Pat. No. 5,238,922, incorporated herein by reference, R1 wherein: X, Y, and Z are independently H2 or O, provided that at least one of these is H2; R! is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, RINH may be absent; R2, R3 and R4 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted iwth an aromatic or heteroaromatic ring; and R5 is H or a straight or branched chain aliphatic group, which may be substituted with an aromatic or heteroaromatic group; f) U.S. Pat. No. 5,340,828, incorporated herein by reference, wherein: X and Y are independently H2 or O, provided that at least one of these is H2; R! is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, R!NH may be absent; R2 and R3 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring; Z is O or S; and n is 0, 1 or 2; g) U.S. Pat. No. 5,340,828, incorporated herein by reference, wherein: X and Y are independently H2 or O, provided that at least one of these is H2; R! is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, RINH may be absent; R2 and R3 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring; Z is O or S; and n is 0, 1 or 2; h) U.S.Pat. No. 5,352,705, incorporated herein by reference, wherein: X and Y are independently H2 or O; Rl is an alkyl group, hydrogen, an acyl group, an alkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbons atoms, which alternatively may be substituted with an aryl group; R2 is the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heterocyclic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; R3 is an aromatic or heteroaromatic ring or in the alternative an alkyl group or an aryl or heteroaryl substituted alkane, wherein the aromatic ring is unsubstituted or in the alternative, substituted with one or more groups which may be alkyl, halo, alkoxy, trifluoromethyl, or sulfamoyl groups, and which may be poly cyclic; i) U.S. Pat. No. 5,326,773; PCT Publication WO 94/10137 and U.S. Serial No. 08/346,701, incorporated herein by reference, or wherein: R! and R^ are independently selected from: hydrogen, a Cl-C6 alkyl group, a Cl-C6 acyl group, an aroyl group, a Cl-C6 alkylsulfonyl group, Cl-C6 aralkylsulfonyl group or arylsulfonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle; R2, R3 and R4 are independently selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted Cl-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups, wherein the aliphatic substituent is optionally substituted with an aryl, heterocycle or C3-C8 cycloalkyl; R^b is a C1-C6 alkyl group, a C 1-C6 acyl group, an aroyl group, a C1-C6 alkylsulfonyl group, C1-C6 aralkylsulfonyl group or arylsulfonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle; R6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring; and n is 0, 1 or 2; j) PCT Publication WO 94/09766 and U.S. Serial No. 07/968,022, incorporated herein by reference, III or wherein: R is selected from: hydrogen, a Cl-C6 alkyl group, a Cl-C6 acyl group, an aroyl group, a Cl-C6 alkylsulfonyl group, C1-C6 aralkylsulfonyl group or arylsulfonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle; R2, R3 and R4 are independently selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted Cl-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups, wherein the aliphatic substituent is optionally substituted with an aryl, heterocycle or C3-C8 cycloalkyl; X is CH2CH2 or trans CH=CH; R6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring; and n is 0, 1 or 2; k) PCT Publication WO 94/10138 and U.S. Serial No. 08/143,943, incorporated herein by reference, or wherein, Rl is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; R2, R3 and R5 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; R4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring; 1) PCT Publication WO 95/00497, incorporated herein by reference, wherein: X is O or H2; m is 1 or 2; n is 0 or 1 ; t is 1 to 4; R and Rl are independently selected from H, Cl-4 alkyl, or aralkyl; R2, R3, R4 ? and R5 are independently selected from: H; Cl-8 alkyl, alkenyl, alkynyl, aryl, heterocycle, unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl, d) halogen, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(0)R6, SO2R 6 , 5) — NR 6 R 7 Y is aryl, heterocycle, unsubstituted or substituted with one or more of: 5) NR6R7, 6) CN, 7) N02, or 8) CF3; W is H2 or O; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, or e) HO, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) N02, or 8) CF3; R6, R7 and R$ are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, g) NRRl, wherein R6 and R^ may be joined in a ring, and R7 and R& may be joined in a ring; and R 9 is Cl-4 alkyl or aralkyl; m) U.S. Serial No. 08/315,059, incorporated herein by reference, or IV wherein: Rl is selected from: a) hydrogen, b) R8S(0)2-, R8C(0)-, (R8)2NC(0)- or R9θC(0)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R θ-, R8s(0)m-, R8C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8)2, or R9θC(0)NR8-; R2a and R2b are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, RSO-, R 8 S(0)m-, R 8 C(0)NR8-, CN, (R8) 2 N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8)2, or R9θC(0)NR8-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 0-, R 8 S(0)m-, R8C(0)NR8-, CN, N0 2 , (R8) 2 N- C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8) 2 , or R90C(0)NR8-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C2O alkyl, C 2 -C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R8) 2 , N0 2 , R80-, R 8 S(0)m-, R8C(0)NR8-, CN, (R8) 2 N-C(NR8)-, R8C(0)-, R80C(0 , N3, -N(R8) , R9θC(0)NR8- and Cl-C 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R8) 2 , N0 2 , R80-, R 8 S(0)m-, R 8 C(0)NR8-, CN, (R8) 2 N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8) 2 , R9θC(0)NR8- and Ci-C 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; or R5a and R5b are combined to form - (CH 2 ) S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR8)- ; R6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: D aryl, 2) heterocycle, 3) -N(R9) 2 , 4) -OR8, or R 11 . X-Y is 7a f) -CH 2 -CH - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R is independently selected from hydrogen, C1-C6 alkyl and aryl; R9 is independently selected from C1-C6 alkyl and aryl; RlO is independently selected from hydrogen and C1-C6 alkyl; RU is independently selected from C1-C6 alkyl; Zl and Z2 are independently H 2 or O, provided that Zl is not O when X-Y is - C(0)N(R7a)- ; m is 0, 1 or 2; q is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; n) U.S. Serial No. 08/315,151, incorporated herein by reference, I wherein: Rl is selected from: a) hydrogen, b) R5S(0) 2 -, R5C(0)-, (R5)2NC(0)- or R6θC(0)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R^O-, R5S(0)m-, R 5 C(0)NR5-, CN, (R5) 2 N-C(NR5)-, R5C(0)-, R5θC(0)-, N3, -N(R5) 2 , or R6θC(0)NR5-; R2a and R2b are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R^O-, R5s(0)nτ-, R5C(0)NR5-, CN, (R5) 2 N-C(NR5)-, R5C(0)-, R5θC(0)-, N3, -N(R5)2, or R6θC(0)NR5-, and c) aryl, heterocycle, cycloalkyl, alkenyl, R^O-, R5S(0)m-, R 5 C(0)NR5-, CN, N02, (R 5 ) 2 N-C(NR5)-, R5C(0)-, R5θC(0)-, N3, -N(R5) 2 , or R6θC(0)NR5-, R3 is selected from: a) unsubstituted or substituted aryl, b) unsubstituted or substituted heterocycle, c) unsubstituted or substituted cycloalkyl, and d) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; X-Y is (O)m f) -CH 2 _ CH 2 - ! R4a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R4b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R5 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R6 is independently selected from Cl-C6 alkyl and aryl; Z is independently H2 or O; m is 0, 1 or 2, provided that m is 0 when R^ = hydrogen ; n is 0, 1, 2, 3 or 4; and t is 3, 4 or 5; and p) U.S. Serial Nos. 08/412,621 and 08/ (Case 19384IA, filed June 6, 1995), incorporated herein by reference, wherein: X and Y are independently O or H2; m is 1 or 2; n is 0 or 1 ; p is 1, 2 or 3; q is 0, 1 or 2; t is 1 to 4; R, Rl and R2 are independently selected from: H, Cl-6 alkyl, or Cl-6 aralkyl; R3 and R4 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C 2 -C6 alkenyl, R60-, R 5 S(0) q -, R7C(0)NR6-, CN, N3, R6θC(0)NR6-, R6R7N-C(NR6R8)-, R6C(0)-, R7R8NC(0)0-, R7R8NC(0)-, R6R7N-S(0) 2 -, -NR6S(0) R5, R6θC(0)0-, -NR6R7 5 or R7R8NC(0)NR6-, c) unsubstituted or substituted cycloalkyl, alkenyl, R60-, R 5 S(0) q -, R6C(0)NR6-, CN, N0 2 , R6R7N-C(NR8)-, R6C(0)-, N3, -NR6R7, halogen or R7θC(0)NR6-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; W is -CHR9- or -NR9- ; Z is unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C 2 -8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle; wherein the substituted group is substituted with one or more of: 1 ) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R , c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) N02, or 9) CF ; R5 is Cl-4 alkyl or aralkyl; R6, R7 and R8 are independently selected from: H, Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, f) — SO 2 R 5 , or g) -NR6R7, 0 Γ R6 and R7 may be joined in a ring, and R7 and R8 may be joined in a ring; R9 is selected from: H, Cl-4 alkyl, C3-6 cycloalkyl, heterocycle and aryl, unsubstituted, monosubstituted or disubstituted with substituents independently selected from: a) Cl-4 alkyl, b) Cl-4 alkoxy, c) aryl or heterocycle, d) halogen, e) HO, o g) — S0 2 R 5 , and h) -NR6R ; V is selected from: -C(Rl 1)=C(R11)-, -C≡C-, -C(O)-, -C(Rl 1) 2 -, -C(ORl l)R l-, -CN(R11) 2 R11-, -OC(Rl )2-, -NR 1C(R11)2-, -C(R l) 2 0-, -C(R11) 2 NR11-, -C(0)NRl l-, -NRl lC(O)-, O, -NC(0)Rl l-, -NC(0)ORl l-, -S(0)2N(Rl l)-, -N(Rl l)S(0)2-, or S(0)m; RlO and Rl 1 are independently selected from hydrogen, Cl-C6 alkyl, C 2 -C4 alkenyl, benzyl and aryl; or the pharmaceutically acceptable salt thereof. The composition of the instant invention may alternatively or in addition comprise a protein substrate-competitive inhibitor that does not incorporates a cysteinyl or sulfhydryl containing moiety at the N- terminus of the molecule. The lack of a sulfhydryl offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Thus the following compounds, well known in the art, are also useful as protein substrate-competitive inhibitors in the instant invention: q) PCT Publication WO 95/09001 and U.S. Serial No. 08/314,987, incorporated herein by reference, or IV Rl is selected from: a) heterocycle, and b) Cl-ClO alkyl, which is substituted with heterocycle and which is optionally substituted with one or more of C1-C4 alkyl, hydroxy or amino groups; R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-C 2 0 alkyl, C 2 -C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N0 2 , R80-, R9S(0)πr, R S C(0)NR8-, CN, (R8) 2 N- C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8) 2 , R9θC(0)NR8- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2a and R2b are combined to form - (CH 2 ) S - ; R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R8)2, N0 2 , R80-, R9S(0)m-, R S C(0)NR8-, CN, (R8) 2 N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8) , R9θC(0)NR8- and Cl-C 2 0 alkyl,, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH 2 )s - ; R5 and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-C 2 0 alkyl, C 2 -C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R8) 2 , N0 2 , R80-, R9S(0)m-, R S C(0)NR8-, CN, (R8) 2 N-C(NR8)-, RδC(O)-, R8θC(0)-, N3, -N(R8) 2 , R9θC(0)NR8- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH 2 )s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR8)- ; R6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R9) 2 , 4) -OR8, or b) X-Y is = ) Y^\ * t) -CH 2 _ CH 2 - J R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R is independently selected from hydrogen, C1-C6 alkyl and aryl; R9 is independently selected from C1-C6 alkyl and aryl; RIO is independently selected from hydrogen and C1-C6 alkyl; Rl 1 is independently selected from C1-C alkyl; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 or 2; and s is 4 or 5; r) PCT Publication WO 95/09000 and U.S. Serial No.08/143,943, incorporated herein by reference, III and IV wherein: Vis CH2,0,S,HN,orR7N; R2, R3, R4 and R5 are independently the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; X-Y is 7 o c) Y^ (0) m d) f) -CH 2 -CH - ; R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring; R7 is an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, which may be substituted with an aromatic or heteroaromatic group; Z is H2 or O; m is 0, 1 or 2; n is 0, 1 or 2; and o is 0, 1, 2 or 3; s) U.S. Serial No. 08/315,171, incorporated herein by reference, - (CR 1 ι a a 2 ) n - W and IV wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (RlO) N-C(NRlO)-, RlOC(O)-, or RIOQC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or R11OC(O)NR10- ; Rib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, aikynyl, (R10) 2 N-C(NR10)-, RlOC(O)-, or RlQθC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, RHS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-; provided that Rib is not R1 C(O)NR10- when R ia is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, Nθ2, R 10 O-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lθC(O)NRl0- and Cl-C 2 0 alkyLand d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2a and R2b are combined to form - (CH 2 ) S - ; R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-C 0 alkyl, C 2 -C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , RlOO-, RHS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0- and Cl-Qo alkyl, and d) C1-C alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; R5a and R5b independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , R11OC(O)NR10- and Cl-C 2 Q alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH 2 ) S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORlO)- ; R6 IS a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: D aryl, 2) heterocycle, 4) -ORlO, or b) R 12 O Y^O^R 3 . X-Y is (0)m f) -CH 2 _ CH - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl -, CN, N02, Rlθ2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, RHS(0)m-, Rl°C(0)NH-, CN, H2N- C(NH)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or Rl lOC(0)NH-; R9 is selected from: hydrogen , C1-C6 alkyl , RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N0 2 , N3, -N(RlO) 2 , and Rl lθC(O)NRl0-; provided that R9 is not R!0C(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; RU is independently selected from C1-C6 alkyl and aryl; Rl is independently selected from hydrogen and C1-C6 alkyl; R 3 is C1-C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0)m-, -O-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a or -N[C(0)R7a]- ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0) m - ; p is 0, 1, 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C1-C6 lower alkyl ; q is 0, 1 or 2; r is 0 or 1; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; t) U.S. Serial No. 08/315,046, incorporated herein by reference, R III and IV wherein: Rl is hydrogen, Cl-C6 alkyl or aryl; R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 9 0-, RlOS(0)m-, R9C(0)NR9-, CN, (R9) 2 N- C(NR9)-, R9C(0)-, R9θC(0)-, N3, -N(R9) 2 , Rl0θC(O)NR9- and Cl-C 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2a and R2b are combined to form - (CH 2 ) S - R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, Nθ2, R9θ-, Rl S(O)m-, R 9 C(0)NR9-, CN, (R9) 2 N- C(NR9)-, R9C(0)-, R90C(0)-, N3, -N(R9) 2 , Rl0θC(O)NR9- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH 2 )s - ; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Ci-C 0 alkyl, C 2 -C 2 0 aikenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N0 2 , R9θ-, Rl0S(O)m-, R9C(0)NR9-, CN, (R9) 2 N- C(NR9)-, R9C(0)-, R9θC(0)-, N3, -N(R9) 2 , Rl0θC(O)NR9- and Cl-C 2 0 alkyl, and d) C1-C alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH 2 )s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m, -NC(O)-, and -N(COR9)- ; R6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(RlO) 2 , 4) -OR9, or b) R 2 O X-Y is R 7a f) -CH 2 -CH 2 - j R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R8a and R8b are independently selected from: hydrogen, F, Cl, Br, N0 2 , RHO-, Rl0S(O) m -, CN, R9C(0)NR9-, (R9) 2 N-C(NR9)-, R9C(0)-, R9θC(0)-, N3, -N(R9) , Rl0θC(O)NR9-, Cl-Qo alkyl, aryl, heterocycle or Cl-C 2 0 alkyl substituted with aryl or heterocycle; R9 is independently selected from hydrogen, C1-C6 alkyl and aryl; RlO is independently selected from C1-C6 alkyl and aryl; RU is independently selected from hydrogen, C1-C6 alkyl and aryl, provided Rl 1 is C1-C6 alkyl when n is 0; Rl2 is independently hydrogen or C1-C6 alkyl; Rl3 is C1-C6 alkyl; is aryl or 1,2,3,4-tetrahydronaphthyl; Z is independently H2 or O; m is 0, 1 or 2; n is independently 0 to 4; p is 0 or 1 ; q is 0, 1 or 2; and s is 4 or 5; u) U.S. Serial No. 08/314,974, incorporated herein by reference, V - A 1 (CR 1 2 ) n A 2 (CR 1 2 ) n - or - A 1 (CR 1 2 ) n A 2 (CR 1 2 ) n - IV wherein: Rl is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl O-, R !S(0) m -, R1°C(0)NR10-, CN, N02, (Rl ) 2 N-C(NRlO)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO) , or Rl lθC(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R OO-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)NRl0-; R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, Nθ2, R 10 O-, Rl lS(0)m-, R1°C(0)NR10-, CN, (RlO) N-C(NRl )-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl - and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2a and R2b are combined to form - (CH 2 ) S - ; R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-C 2 0 alkyl, C 2 -C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , RlOO-, RHS(0) m -, R1°C(0)NR1 -, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, Nθ2, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , R11OC(O)NR10- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH 2 ) S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORlO)- ; a) substituted or unsubstituted Cl-C8 alkyl, wherein the substituent on the alkyl is selected from: l) aryl, 2) heterocycle, 3) -N(Rl l) 2 , 4) -ORlO, or X-Y is R 7b f) -CH 2 -CH 2 - R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N0 2 , R!0 2 N-C(NR10)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NH-, CN, H 2 N-C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(0)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl°C(O)NRl0-, CN, N0 2 , (RlO) 2 N- C(NRlO)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl C(O)NRl -, CN, (R10) 2 N-C(NR10)-, R10C(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl 10C(0)NR10- ; RlO is independently selected from hydrogen, C1-C6 alkyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Rl2 is independently selected from hydrogen and C1-C6 alkyl; Rl3 is independently selected from C1-C6 alkyl; Al and A2 are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NRl0-, O, -N(R10)-, -NRlOC(O)-, -S(0) 2 N(RlO)-, -N(Rl0)S(O) 2 - or S(0) m ; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C 2 0 alkenyl ; provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A is S(0)m or a bond; W is a heterocycle; Z is independently H 2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; and s is 4 or 5; v) U.S. Serial Nos. 08/315,161; 08/399,282; and 08/ (Case 19308IB, filed June 6, 1995), incorporated herein by reference, wherein: Rl and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, N0 2 , (Rl ) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, c) C1-C alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C -C6 alkenyl, C 2 -C6 alkynyl, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)-NRl0-; R2a and R2b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C 2 -C6 alkenyl, RIOO-, RllS(0)m-, R1°C(0)NR10-, CN, N3, (RlO) 2 N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl lθC(O)NRl0-, c) aryl, heterocycle, C3-C 10 cycloalkyl, C 2 -C6 alkenyl, RlOO-, R n S(0)m-, Rl°C(O)NRl0-, CN, N0 2 , (R1 ) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , or RHOC(0)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , Rl O-, Rl lS(0) m -, R10C(0)NR10-, CN, (RlO) 2 N-C(NRl )-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) , Rl lθC(O)NRl0- and Cl-C 2 Q alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH 2 ) S - ; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-C 2 0 alkyl, C 2 -C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, CF3, N(RlO) 2 , N0 2 , RlOO-, RHS(0) m -, Rl0C(O)NRl -, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0- and Cl-C 2 0 alkyl, and d) C1-C alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m, -NC(O)-, and -N(CORl°)- ; R6 is a) substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1-C6 alkyl, 2) aryl, 3) heterocycle, 5) -ORlO, or X-Y is c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl C(O)NRl0-, CN, N0 2 , R!0 2 N-C(NR10)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl0C(O)NH-, CN, H 2 N-C(NH)-, Rl C(O)-, Rl θC(O)-, N3, -N(RlO)2, or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C 2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, N0 2 , (Rl ) 2 N- C-(NRlO)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or RllOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, RUS(0) m -, R 10 C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0- ; RlO is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl; RU is independently selected from -C6 alkyl and aryl; R 12 is hydrogen or C 1 -C6 alkyl; Rl3 is C1-C6 alkyl; Al and A2 are independently selected from: a bond, -CH=CH-, -CΞC-, -C(O)-, -C(O)NRl0-, -NRIOC(O)-, O, -N(R1 )-, -S(O)2N(Rl )-, -N(RlO)S(0)2-, or S(0) m ; provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if A is a bond, n is 0 and A2 is S(0)m; W is a heterocycle; Z is independently H or O; w) U.S. Serial Nos. 08/413,137and 08/412,830 , incorporated herein by reference, IV wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, RlOO-, R n S(0) m -, Rl°C(O)NRl -, CN, Nθ2, (RlO) N-C(NRlO)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R OO-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, (R1 ) 2 N-C(NR10)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)- NR10-; R2a and R2b are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R 1 OO-, Rl lS(0)m-, Rl°C(O)NRl -, CN, N3, (RlO)2N-C(NRlO)-, Rl C(O)-, Rl θC(O)-, -N(RlO) 2 , or Rl lθC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, R OO-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, N0 2 , (RlO) 2 N- C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; R3a and R3b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(Rl ) 2 , N0 2 , Rl O-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , R11QC(O)NR10- and Cl-C 2 Q alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3a and R3b are combined to form - (CH 2 ) S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m, -NC(O)-, and -N(CORl )- ; R4 and R5 are independently selected from: a) hydrogen, and R6 IS a) substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(Rl l) 2 , 4) -ORlO, or R7 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl0C(O)NRl0-, CN, N0 2 , R10 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , or Rl lθC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, RHS(0) m -, Rl°C(0)NH-, CN, H 2 N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl0θC(O)NH-; R8 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)πr, R 10 C(O)NRl0-, CN, N0 , (Rl ) 2 N-C-(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO)2, or RHθC(O)NRl -, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-; RIO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Rl2 is independently selected from hydrogen and -C6 alkyl; Rl3 is independently selected from C1-C6 alkyl; Al and A2 are independently selected from: a bond, -CH=CH-, -CHC-, -C(O)-, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)-, -S(O)2N(Rl0)-, -N(Rl0)S(O)2-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if A 1 is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; W is a heterocycle; Z is independently H 2 or O; x) U.S. Serial Nos. 08/412,626 and 08/412,828, incorporated herein by reference, wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R OO-, R π S(0)m-, Rl°C(O)NRl -, CN, N0 2 , (RlO)2N-C(NRlO)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, R n S(0)m-, Rl°C(O)NRl0-, CN, (R1 ) 2 N-C(NR10)-, RlOC(O)-, Rl θC(O)-, N3, -N(Rl ) 2 , or RHθC(O)- NR10-; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-C 0 alkyl, C 2 -C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , Rl O-, RllS(0)m-, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , RHOC(O)NR10- and Ci-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R 10θ-, R n S(0) m -, Rl°C(O)NRl0-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, Rl θC(O)-, -N(Rl ) 2 , or Rl lθC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N0 2 , (Rl ) 2 N- C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) , or Rl lθC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lθC(O)NRl - and Cl-C 0 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH 2 )s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORlO)- ; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl -, CN, N0 , R10 2 N-C(NR10)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl°C(0)NH-, CN, H 2 N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl°C(O)NRl0-, CN, N02, (Rl°)2N-C- (NRlO)-, RlOC(O)-, R10OC(O , N3, -N(RlO) 2 , or RllOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, RllS(0) m -, R1°C(0)NR10-, CN, (Rl ) N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Rl2 is a) substituted or unsubstituted C 1 -C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from: 1) aryl, 4) -ORl°, or Rl3 is independently selected from hydrogen and C1-C6 alkyl; Rl4 is independently selected from C1-C6 alkyl; Al and A are independently selected from: a bond, -CH=CH-, -C≡C-, -C(0)-, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)-, -S(0) 2 N(RlO)-, -N(RlO)S(0) 2 -, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A is S(0)m", W is a heterocycle; X, Y and Z are independently H2 or O; y) U.S. Serial Nos. 08/412,829 and 08/ (Case 19422IA, filed June 6, 1995), incorporated herein by reference, B wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RHS(0) m -, R10C(O)NR10-, CN, NO2, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, RlOO-, RHS(0) m -, R1°C(0)NR10-, CN, (Rl ) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)-NRl0-; R2 and R3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C 2 -8 alkenyl, unsubstituted or substituted C 2 -8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl, b) (CH ) p OR6, c) (CH 2 ) P NR6R7, d) halogen, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(0)R 6 , SO2R 6 , 5) — NR 6 R 7 or or R and R3 are attached to the same C atom and are combined to form (CH 2 )u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORlO)- ; R4 is selected from H and CH3; and any two of R2, R3 and R4 are optionally attached to the same carbon atom; R6, R7 and R^a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, f) — S0 2 R 11 , or g) N(RlO) 2; or R6 and R7 may be joined in a ring; R7 and R^a m ay be joined in a ring; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, R OO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N0 2 , R10 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl 10C(0)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C -C6 aikynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl0C(O)NH-, CN, H 2 N-C(NH)-, Rl C(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) aikenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R OO-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, Nθ2, (RlO) 2 N-C-(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (Rl ) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-; RlO is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A2 are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NRl0-, -NRIOC(O)-, O, -N(R1 )-, -S(0)2N(RlO)-, -N(Rl )S(0)2-, or S(0) m ; G is H 2 or O; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Cl-C 2 0 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C 2 -C 2 0 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; W is a heterocycle; X is -CH2-, -C(=0)-, or -S(=0) m -; Y is aryl, heterocycle, unsubstituted or substituted with one or more of: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR 7 5 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, Zis z) U.S. Serial No. 08/ , (Case 19466, filed June 6, 1995), incorporated herein by reference, V - A 1 (CR 1a 2 ) n A (CR 1a 2 ) n - wherein: Rla is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C2O alkenyl, C - C20 alkynyl, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, N02, (RlO)2N-C(NRlO)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C2-C20 alkenyl, C 2 -C 2 0 alkynyl, R OO-, RHS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)-NRl0-; Rib is independently selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C 2 -C 2 0 alkenyl, C2-C 2 0 alkynyl, RlOO-, RHS(0) m -, CN, N0 2 , (R1 ) 2 N-C(NR10)-, R10C(O)-, RlOθC(O)-, N3 or -N(Rl ) , c) C1-C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, C3-C10 cycloalkyl, C 2 -C 2 0 alkenyl, C -C 2 0 alkynyl, RlOO-, Rl lS(0)ιrr, CN, (R1 ) 2 N-C(NR10)-, RlOc(O)-, RlOθC(O)-, N3 or -N(RlO) 2; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-C 2 0 alkyl, substituted or unsubstituted C 2 -C 2 0 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(Rl ) 2 , N0 2 , Rl O-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, Rl θC(O)-, N3, -N(Rl ) 2 , Rl lθC(O)NRl0- and Cι-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R7 to form a ring such that R4, R5, Rl3a and Rl3b are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by C 2 -C 2 0 alkenyl, RlOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, N3, (Rl°)2N- C(NRlO)-, RlOC(O)-, -N(RlO) , or Rl lθC(O)NRl0-, c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C 2 - C 2 0 alkenyl, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, N0 2 , (RlO) 2 N-C(NRlO)-, R10C(O)-, N3, -N(RlO) 2 , or Rl lθC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R6 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C2O alkynyl, C1-C2O perfluoroalkyl, allyloxy, F, Cl, Br, RlOO-, RHS(0) m -, Rl°C(O)NRl0-, CN, NO2, Rl0 N-C(NRlO)-, RlOC(O)-, N3, -N(RlO) 2 , (Rl2) 2 NC(0)- or Rl lOC(O)NRl -, and c) C1-C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C 2 0 alkenyl, C 2 -C 2 0 alkynyl, C - C 2 0 perfluoroalkyl, F, Cl, Br, RlOO-, RllS(0) m -, Rl C(O)NH-, CN, H 2 N-C(NH)-, RlOC(O)-, N3, -N(RlO) , or Rl0θC(O)NH-; R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C 1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; R8 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C 2 -C 2 0 alkenyl, C 2 -C 2 0 alkynyl, C 1 -C 2 0 perfluoroalkyl, allyloxy, F, Cl, Br, R 1 OO-, RllS(0)m-, Rl°C(O)NRl0-, -S(O) 2 NRl 2 , CN, N0 2 , Rl0 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C2O alkynyl, C 2 - C20 perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl θC(O)NH-; R9 is selected from: a) hydrogen, b) C2-C20 alkenyl, C 2 -C 2 0 alkynyl, C 2 -C 2 o perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, N0 2 , (RlO) 2 N-C-(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 2 -C 2 0 perfluoroalkyl, F, Cl, Br, Rl O-, Rl lS(0) m -, Rl C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)~, RlOc(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , or RHOC(O)NR10- ; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Rl2 is independently selected from hydrogen, C1-C6 alkyl and aryl, or (Rl2) 2 forms - (CH 2 ) S - ; Al> A2 and A3 are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(0)NR7-, -NR7C(0)-, O, -N(R7)-, -S(0) 2 N(R7)-, -N(R7)S(0) 2 -, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0) m ; W is a heterocycle; Z is independently H2 or O; s is 4 or 5; and t is 3, 4 or 5; and aa) U.S. Serial No. 08/449,038, incorporated herein by reference, wherein: Rla and Rib are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O-, R9s(0) m -, R8C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8c(0)-, R8θC(0)-, N3, -N(R8) 2 , or R9θC(0)NR8-, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C6 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, R80-, R9S(0) m -, R S C(0)NR8-, CN, (R8) 2 N-C(NR8)-, R8c(0)-, R8θC(0)-, N3, -N(R8) 2 , or R9θC(0)-NR8-; R2a, R2b and R3 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R80-, R9S(0)m-, R S C(0)NR8-, CN, N3, (R S )2N-C(NR8)-, R8C(0)-, R80C(0)-, -N(R8) 2 , or R9θC(0)NR8-, c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R8θ-, R 9 S(0) m -, R8C(0)NR8-, CN, Nθ2, (R8) 2 N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8) , halogen or R9θC(0)NR8-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R4 and R5 are independently selected from: a) hydrogen, and R6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1-C6 perfluoroalkyl, F, Cl, Br, R80-, R9s(0)m-, R S C(0)NR8-, CN, N0 2 , R8 N- C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8) 2 , or R9θC(0)NR8-, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 aikenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R80-, R9S(0)m-, R 8 C(0)NH-, CN, H2N-C(NH)-, R8C(0)- , R80C(0)-, N3, -N(R8) 2 , or R80C(0)NH-; R7 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, Br, R80-, R 9 S(0)m-, R 8 C(0)NR8-, CN, NO2, (R 8 )2N-C- (NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R 8 ) 2 , or R9θC(0)NR8-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, Br, R80-, R9S(0) m -, R S C(0)NR8-, CN, (R8) 2 N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8) 2 , or R9θC(0)NR8- ; R is independently selected from hydrogen, C1-C alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl; R9 is independently selected from C1-C6 alkyl and aryl; RlO is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl; Al and A2 are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(0)NR8-, -NR8C(0)-, O, -N(R8)-, -S(0)2N(R8)-, -N(R8)S(0)2-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; W is a heterocycle; Y is selected from: a bond, -C(R1°)=C(R10)-, -C≡C-, -C(O)-, -C(RlO) 2 -, -C(ORl0)Rl0-, -CN(RlO) 2 RlO-, -OC(RlO)2-, -NR10C(R10) 2 -, -C(RlO) 2 0-, -C(RlO) 2 NRlO-, -C(O)NRl0-, -NRI C(O)-, O, -NC(O)Rl0-, -NC(O)ORl0-, -S(O)2N(Rl0)-, -N(RlO)S(0)2-, or S(θ)m; or the pharmaceutically acceptable salts thereof. The method and composition of the instant invention may alternatively or in addition comprise a protein substrate-competitive inhibitor obtained by fermentation of cultures of novel organisms. In particular, the compounds disclosed in the following patents and publications may be useful as a protein substrate-competitive inhibitor component of the instant composition: U.S. Pat. No. 5,420,334; and 08/435,047. Those patents and publications are incorporated herein by reference. In addition, compounds described in the following patents and publications may also be utilized as a protein substrate-competitive inhibitor component of the instant composition: U.S. Pat. No. 5,420,245; European Pat. Publ. 0 618 221 ; PCT Pat. Publs. WO 94/26723; WO 95/08542 ; WO 95/11917; and WO 95/12612. Those patents and publications are incorporated herein by reference. Specific examples of protein substrate-competitive inhibitors useful in the method and composition of the invention are: Compound A: or the pharmaceutically acceptable salts thereof. Other specific examples of protein substrate-competitive inhibitors useful in the compositions of the invention are: 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-propyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-methyl- 3,4-E-octenoyl-homserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-ethyl-3,4- E-octenoyl-homserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptoproρylamino]-6(S)-methyl-2(R)-i-propyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptoρropylamino]-6(S)-methyl-2(R)-n-butyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-mefhyl-2(R)-s-butyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-t-butyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)- cyclohexyl-3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)- cyclopentyl-3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-benzyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6-methyl-2(R)-i-propyl-3,4- E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-i-propyl- 3,4-E-octenoyl-methionine, and the corresponding methyl ester, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-butyl- 3,4-E-octenoyl-methionine, and the corresponding methyl ester, 5(S)-[2(R)-amino-3-mercaptoproρylamino]-6(S)-methyl-2(R)-benzyl- 3,4-E-octenoyl-methionine, and the corresponding methyl ester, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-propyl- octanoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-benzyl- octanoyl-homoserine, and the corresponding homoserine lactone, N-(3-phenyl-2(S)-(mercaptopropionylamino)prop- 1 -yl)isoleucyl- methionine, N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine, N-(3-mercaptopropyl)isoleucyl-phenylalanyl-methionine, N-(3-mercaptopropyl)valyl-isoleucyl-methionine, N-(2(R)-amino-3-mercaptoρropyl)valyl-isoleucyl-methionine, N-(3-methyl-2(S)-(cysteinylamino)but- 1 -yl)phenylalanyl-methionine, N-(3-methyl-2(S)-(mercaptopropionylamino)but-l-yl)-phenylalanyl- methionine, N-[2(S)-(2(R)-amino-3-mercaptoρroρylamino)-3(S)methylpentyl]- phenylalanyl-methionine, N-[2(S)-(3-mercaptopropylamino)-3(S)methylpentyl]-phenylalanyl- methionine, N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-(methionine sulfone), N-(2(R)-amino-3-mercaptopropyl)isoleucyl)-(p-iodophenylalanyl)- methionine, N-[2(R)-(cysteinyl-isoleucylamino)-3(S)-methylpentyl]-methionine, N-[2(R)-(N'-(2(R)-amino-3-mercaptoρropyl)-isoleucylamino)-3-phenyl- propyljmethionine, N-[2(R)-(N , -(2(R)-amino-3-mercaptopropyl)-isoleucylamino)-3(S)- methylpentyl]methionine, N-(3-mercaptopropyl)valyl-isoleucyl-methionine methyl ester, N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine ethyl ester, N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine benzyl ester, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-phenethylamide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-benzylamide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-3-methylbutylamide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-3-phenylpropylamide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucyl-L-phenylalaninol, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-N'-methylbenzylamide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4- methoxybenzyl)amide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dichloro- benzyl)amide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-trifluoromethyl- benzyl)amide, N- [2(R)- Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dichloro- phenethyl)amide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2-benzimidazol- ylmethyl)amide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(l-indanyl)amide, N-[2(R)-Amino-3-mercaptoρropyl]-L-isoleucine-(2,4-dimethyl- benzyl)amide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3-dichloro- benzyl)amide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-sulfamoyl- benzyl)amide, N-[2(R)-Amino-3-mercaρtopropyl]-L-isoleucineanilide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dimethyl- phenyl)amide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3-dimethyl- phenyl)amide, L-Cysteinyl-L-isoleucine-phenethylamide, N-[2(S)-[2(R)-Amino-3-mercaptopropylamino]-3-methylpentyl]- phenethylamide, N-(2(R)-Amino-3-mercaptopropyl)-L-alaninebenzylamide, N-Benzyl-[2(S)-2(R)-Amino-3-mercaptopropyl)-amino]butyramide, N-(2(R)-Amino-3-mercaptopropyl)-L-norleucinebenzylamide, N-(2(R)-Amino-3-mercaptopropyl)-L-norvalinebenzylamide, N-(2(R)-Amino-3-mercaρtopropyl)isoleucyl-ρhenylalanyl-homoserine, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homoserine, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl-homoserine lactone, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homoserine lactone, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl-homocysteine lactone, N-[2(S)-(2(R)-Amino-3-mercaptopropyl)-3(S)-methylpentyl]-isoleucyl- homoserine lactone, N-[N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl]-3(S)- amino-tetrahydropyran-2-one, N-[N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl]-3(S)-amino- tetrahydropyran-2-one, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homocysteine lactone, N-[2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-mefhyl pentyl]isoleucyl-homoserine, N-[N'-(2(R)-Amino-3-mercaρtopropyl)isoleucyl-phenylalanyl]-3(S)- amino-4-hydroxypentanoic acid, N-[N l -(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl]-3(S)-amino- 4-hydroxypentanoic acid, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-isoleucyl-homoserine, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-isoleucyl-homoserine lactone, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-phenylalanyl-homoserine, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-phenylalanyl-homoserine lactone, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methyl-butyl]-N- methyl-phenylalanyl-homoserine, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methyl-butyl]-N- methyl-phenylalanyl-homoserine lactone, 3(S)- { N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methyl- pentyl]-N-methyl-isoleucylamino}-3-methyltetra-hydropyran-2-one, 2(S)-{N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methyl- pentyl]-N-methyl-isoleucylamino}-2-methyl-5-hydroxypentanoic acid, 2(S)-{N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)- methylpentyl]-N-methyl-isoleucylamino}-5-methyl-5-hydroxyhexanoic acid, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-norvalyl-homoserine, N-[2(S)-(2(R)-amino-3-mercaptoρropylamino)-3(S)-methylpentyl]-N- methyl-norvalyl-homoserine lactone, N-[2(S)-(2(R)-amino-3-mercaptoproρylamino)-3(S)-methylpentyl]-N- methyl-isoleucyl-methionine, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-isoleucyl-methionine methyl ester, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-phenylalanyl-methionine, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-phenylalanyl-methionine methyl ester, 3(S)- { N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methyl- pentyll-N-methyl-isoleucylamino}-6,6-dimethyl-tetrahydropyran-2-one, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-norvalyl-methionine, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-norvalyl-methionine methyl ester, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-D-norvalyl-homoserine, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N- methyl-D-norvalyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercaρto]propylamino-3(S)-methyl]- pentyloxy-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-2-methyl-3-ρhenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-4-pentenoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-4-pentenoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxypentanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxypentanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]proρylamino-3(S)-methyl]- pentyloxy-4-methylpentanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-4-mefhylpentanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]proρylamino-3(S)-methyl]- pentyloxy-3-methylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-methylbutanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-phenylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-phenylbutanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentylthio-2-methyl-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]proρylamino-3(S)-methyl]- pentylthio-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-phenylpropionyl-methionine methyl ester, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]ρropylamino-3(S)-methyl]- pentyloxy-3-phenylpropionyl-methionine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-phenylpropionyl-methionine sulfone isopropyl ester, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]ρropylamino-3(S)-methyl]- pentyloxy-3-phenylpropionyl-methionine sulfone, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone methyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-naphth-l-yl-propionyl-methionine sulfone methyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-naphth-l-yl-propionyl-methionine sulfone, 2-(S)- [2(S)- [2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-methybutanoyl-methionine methyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]proρylamino-3(S)-methyl]- pentyloxy-3-methybutanoyl-methionine, Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)- methyl]pentyloxy-3-phenylpropionyl-homoserine lactone, Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)- methyl]pentyloxy-3-phenylpropionyl-homoserine, Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercaρto]propylamino-3(S)- methyl]pentyloxy-3-methylbutanoyl-methionine methyl ester. l-[2-(R)-Amino-3-mercaρtoρropyl]-2(S)-(l-butyl)-4-(2,3-dimethyl- benzoyl)piperazine dihydrochloride 1 - [2(R)-Amino-3-mercaptopropyl]-2(S)-(n -butyl)-4-( 1 - naphthoyl)piperazine l-[2(R)-Amino-3-mercaρtopropyl]-2(S)-benzyl-4-[l-(2,3- dimethyl)benzoyl]piperazine l-[2(R)-Amino-3-mercaptoρroρyl]-2(S)-(2-methoxy)ethyl-4-[l-(2,3- dimethyl)benzoyl]piperazine l-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-methylthio)ethyl-4-[l-(2,3- dimethyl)benzoyl]piperazine l-[2(R)-Amino-3-mercaptopropyl]-2(S)-(n -butyl)-4-[7-(2,3- dihydrobenzofuroyl)]piperazine 1 -(2(R)-Amino-3-mercaptopropyl)-4-( 1 -naphthoyl)-2(S)- pyridinylcarboxyl-4-piperazine dihydrochloride Methyl 4-(2(R)-amino-3-mercaptopropyl)- 1 -( 1 -naphthyl- methyl)piperazine-2-carboxylate hydrochloride l-[2(R)-Amino-3-mercaptoproρyl]-2(S)-(2-methoxyethyl)-4-(l- naphthoyl)piperazine l-[2(R)-Amino-3-mercaρtopropyl]-2(S)-« -butyl-4-(8- quinolinylcarbonyl)piperazine l-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-(l-propoxy)ethyl)-4-(l- naphthoyl)piperazine l-[2(R)-Amino-3-mercaptopropyl]-2(S)-(3-methoxy-l-propyl)-4-(l- naphthoyl)piperazine l-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-(l-propoxy)ethyl)-4-(8- quinolinoyl)piperazine l-[2(R)-Amino-3-mercaρtopropyl]-2(S)-[(3-pyridyl)methoxyethyl)]-4-(l- naphthoyl)piperazine l-[2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2-phenylsulfonyl- ethyl)piperazine dihydrochloride bis- 1,1'- [2(R)- Amino-3-(2(S)-(2-methoxyethyl)-4-naphthoyl- 1 - piperazinyl)]propyl disulfide tetrahydrochloride bis- 1 , 1 '-[2(R)-Amino-3-(4-naphthoyl-2(S)-(2-phenylsulfonylethyl)- 1- piperazinyl)]propyl disulfide tetrahydrochloride 1 - [2(R)- Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2- cyclopropyloxyethyl)piperazine dihydrochloride l-[2(R)-Amino-3-mercaptopropyl]-4-(l-naphthoyl)-2(S)-(4- acetamidobutyl)piperazine dihydrochloride l-[2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2- cyclopropylmethylsulfonylethyl)piperazine dihydrochloride Pyroglutamyl-valyl-phenylalanyl-methionine Pyroglutamyl-valyl-phenylalanyl-methionine methyl ester; Pyroglutamyl-valyl-isoleucyl-methionine; Pyroglutamyl-valyl-isoleucyl-methionine methyl ester; Nicotinoyl-isoleucyl-phenylalanyl-methionine; Nicotinoyl-isoleucyl-phenylalanyl-methionine methyl ester; N-[2(S)-(L-Pyroglutamylamino)-3-methylbutyl]phenylalanyl-methionine; N-[2(S)-(L-Pyroglutamylamino)-3-mefhylbutyl]phenylalanyl-methionine methyl ester; N-[5(S)-(L-Pyroglutamylamino)-6(S)-methyl-2(R)-butyl-3,4(E)- octenoyl]-methionine; N-[5(S)-(L-Pyroglutamylamino)-6(S)-methyl-2(R)-butyl-3,4(E)- octenoyl] -methionine methyl ester; N-[5(S)-((Imidazol-4-yl)acetylamino)-6(S)-methyl-2(R)-butyl-3,4(E)- octenoyl]-methionine; N-[5(S)-((Imidazol-4-yl)acetylamino)-6(S)-methyl-2(R)-butyl-3,4(E)- octenoyl] -methionine methyl ester; N-[5(S)-((Imidazol-4-ylcarbonylamino)-6(S)-methyl-2(R)-butyl-3,4(E)- octenoylj-methionine; N-[5(S)-((Imidazol-4-ylcarbonylamino)-6(S)-methyl-2(R)-butyl-3,4(E)- octenoyl] -methionine methyl ester; N-[2(S)-(2(S)-(Imidazol-4-yl)acetylamino)-3(S)-methylpentyloxy)-3- phenylpropionyl] -methionine ; N-[2(S)-(2(S)-(Imidazol-4-yl)acetylamino)-3(S)-methylpentyloxy)-3- phenylpropionyl] -methionine methyl ester; N-[2(S)-(2(S)-Pyroglutamylamino-3(S)-methylρentyloxy)-3- pheny lpropionyl] -methionine ; N-[2(S)-(2(S)-Pyroglutamylamino-3(S)-methylpentyloxy)-3- phenylpropionyl] -methionine methyl ester; N-[2(S)-(2(S)-Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyloxy)-3- phenylpropionylj-methionine; N-[2(S)-(2(S)-Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyloxy)-3- phenylpropionyl] -methionine methyl ester; N-[2(S)-(2(S)-((3-Picolinyl)amino)-3(S)-methylpentyloxy)-3- pheny lpropionyl] -methionine ; N-[2(S)-(2(S)-((3-Picolinyl)amino)-3(S)-methylpentyloxy)-3- phenylpropionyl] -methionine methyl ester; N-[2(S)-(2(S)-((Histidyl)amino)-3(S)-methylpentyloxy)-3- phenylpropionyl]-methionine; N-[2(S)-(2(S)-((Histidyl)amino)-3(S)-methylpentyloxy)-3- phenylpropionyl] -methionine methyl ester; N-Benzyl-N-[2(S)-((Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyl]- gly cy 1-methionine ; N-Benzyl-N-[2(S)-((Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyl]- glycyl-methionine methyl ester; N-Benzyl-N-[2(S)-((Imidazol-4-ylacetyl)amino)-3(S)-methylpentyl]- glycyl-methionine; N-Benzyl-N-[2(S)-((Imidazol-4-ylacetyl)amino)-3(S)-methylpentyl]- glycyl-methionine methyl ester; N-Benzyl-N-[2(S)-((Pyroglutamyl)amino)-3(S)-methylpentyl]-glycyl- methionine; N-Benzyl-N-[2(S)-((Pyroglutamyl)amino)-3(S)-methylpentyl]-glycyl- methionine methyl ester; N-(l-Naphthylmethyl)-N-[2(S)-((imidazol-4-ylcarbonyl)amino)-3(S)- methylpentyl]-glycyl-methionine; N-(l-Naphthylmethyl)-N-[2(S)-((imidazol-4-ylcarbonyl)amino)-3(S)- methylpentyl]-glycyl-methionine methyl ester; - I ll - N-(l-Naphthylmemyl)-N-[2(S)-((imidazol-4-ylacetyl)amino)-3(S)- methylpentyl]-glycyl-methionine; N-( 1 -Naphthylmethyl)-N- [2(S)-((imidazol-4-ylacetyl)amino)-3 (S)- methylpentyl]-glycyl-methionine methyl ester; N-(l-Naphthylmethyl)-N-[2(S)-((pyroglutamyl)amino-3(S)-methyl- pentyl]-glycyl-methionine; and N-(l-Naphthylmethyl)-N-[2(S)-((pyroglutamyl)amino-3(S)-methyl- pentyl]-glycyl-methionine methyl ester; N- [ 1 -(Pyroglutamylamino)cyclopent- 1 -ylmethyl]-N-( 1 -naphthylmethyl)- glycyl-methionine methyl ester N-[ 1 -(Pyroglutamylamino)-cyclopent- 1 -ylmethyl]-N-( 1 -naphthyl- methyl)-glycyl-methionine N-(2(S)-L-Histidylamino-3(S)-methylpentyl)-N-(benzylmethyl)glycyl- methionine methyl ester N-(2(S)-L-Histidylamino-3(S)-methylpentyl)-N-(benzylmethyl)glycyl- methionine N-(2(S)-L-Histidylamino-3 (S)-methylpentyl)-N-( 1 -naphfhylmethyl)- glycyl-methionine methyl ester N-(2(S)-L-Histidylamino-3(S)-methylpentyl)-N-(l-naphthylmethyl)- glycyl-methionine 2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3- methylbutanoyl-methionine methyl ester 2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3- methylbutanoyl-methionine 2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3- methylbutanoyl-methionine methyl ester 2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3- methylbutanoyl-methionine N-(Benzyl)-N-[2(S)-(2-oxopyrrolidin-5(R,S)-ylmethyl)amino-3(S)- methylpentyl]-glycyl-methionine methyl ester N-(Benzyl)-N-[2(S)-(2-oxopyrrolidin-5(R,S)-ylmethyl)amino-3(S)- methylpentyl]-glycyl-methionine N-(Benzyl)-N-{2(S)-[((D,L)-2-thiazolyl)alanyl)amino]-3(S)- methylpentyl}-glycyl-methionine methyl ester N-(Benzyl)-N-{2(S)-[((D,L)-2-thiazolyl)alanyl)amino]-3(S)- methylpentyl } -glycyl-methionine N-(Benzyl)-N-[2(S)-(3-pyridylmethyl)amino-3(S)-methylpentyl]-glycyl- methionine methyl ester N-(Benzyl)-N-[2(S)-(3-pyridylmethyl)amino-3(S)-methylpentyl]-glycyl- methiomne 2(S)-[2(S)-(2-Oxopyrrolidin-5(S)-ylmethyl)amino-3(S)- methylpentyloxy]-3-phenylpropionyl-methionine methyl estr 2(S)-[2(S)-(2-Oxopyrrolidin-5(S)-ylmethyl)amino-3(S)-methyl- pentyloxy]-3-phenylpropionyl-methionine 2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-(l- naphthyl)proρionyl-methionine sulfone methyl ester 2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-(l- naphthyl)propionyl-methionine sulfone 2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-(2- naphthyl)propionyl-methionine sulfone methyl ester 2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-(2- naphthyl)propionyl-methionine sulfone 2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-(l- naphthyl)propionyl-methionine sulfone methyl ester 2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-(l- naphthyl)propionyl-methionine sulfone 2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-(2- naphthyl)propionyl-methionine sulfone methyl ester 2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-(2- naphthyl)propionyl-methionine sulfone N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(3-quinolyl- methyl)glycyl-methionine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(3-quinoly- lmethyl)glycyl-methionine N-(Benzyl)-N-[2(S)-(tetrazol-l-ylacetyl)amino-3(S)-methylpentyl]- glycyl-methionine methyl ester N-(Benzyl)-N-[2(S)-(tetrazol-l-ylacetyl)amino-3(S)-methylpentyl]- glycyl-methionine N-(Benzyl)-N-[2(S)-nicotinoylamino-3(S)-methylpentyl]-glycyl- methionine methyl ester N-(Benzyl)-N-[2(S)-nicotinoylamino-3(S)-methylρentyl]-glycyl- methionine N-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)-glycyl-methionine sulfoxide methyl ester N- [2(S)-(L-Pyroglutamyl)amino-3 (S)-methylpentyl]-N-( 1 - naphthylmethyl)-glycyl-methionine sulfoxide 2(S)-{2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)- methylpentyloxy}-3-phenylpropionyl-methionine sulfone methyl ester 2(S)-{2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)- methylpentyloxy }-3-phenylpropionyl-methionine sulfone 2(S)-{2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)- methylpentyloxy}-3-phenylpropionyl-methionine sulfone methyl ester 2(S)-{2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)- methylpentyloxy } -3-phenylpropionyl-methionine sulfone N- { 2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)-methyl- pentyl}-N-(l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)- methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)-methyl- pentyl}-N-(l-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)- methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N-{2(S)-[(Imidazol-4-yl)methyl]amino-3(S)-mefhylpentyl}-N-(l- naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[(Imidazol-4-yl)methyl]amino-3(S)-methylpentyl }-N-(l- naphthylmethyl)-glycyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-methionine isopropyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-methionine t-butyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(4-quinolyl- methyl)glycyl-methionine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(4-quinolyl- methyl)glycyl-methionine N-{2(S)-[3-(Imidazol-4-yl)propyl]amino-3(S)-methylpentyl}-N-(l- naphthylmethyl)glycyl-methionine methyl ester N-{2(S)-[3-(Imidazol-4-yl)propyl]amino-3(S)-methylpentyl}-N-(l- naphthylmethyl)glycyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylρentyl]-N-(l-naphthyl- methyl)glycyl-norleucine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylρentyl]-N-(l-naρhthyl- methyl)glycyl-norleucine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-glutamine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-glutamine t-butyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-[5-(dimethyl- amino)naphthylsulfonyl]glycyl-methionine methyl ester N-[2(S)-(3-pyridylmethyl)amino-3(S)-methylpentyl]-N-(l-naphfhyl- methyl)glycyl-methionine 2(S)-{2(S)-[2-(Imidazol-4-yl)ethyl]amino-3(S)-methylpentyloxy}-3- phenylpropionyl-methionine sulfone methyl ester 2(S)-{2(S)-[2-(Imidazol-4-yl)ethyl]amino-3(S)-methylpentyloxy}-3- phenylpropionyl-methionine sulfone N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naρhthyl- methyl)glycyl-serine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-(D,L)-serine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naρhthyl- methyl)glycyl-(L,D)-serine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] -N-( 1 -naphthyl- methyl)glycyl-homoserine lactone N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-homoserine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(cinnamyl)- glycyl-methionine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(cinnamyl)- glycyl-methionine N-{2(S)-[2-(Imidazol-4-yl)ethyl]amino-3(S)-methylpentyl}-N-(l- naphthylmethyl)glycyl-methionine methyl ester N-{2(S)-[2-(Imidazol-4-yl)ethyl]amino-3(S)-methylpentyl}-N-(l- naphthylmethyl)glycyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-alanine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-alanine N-[2(S)-(D-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-methionine methyl ester N-[2(S)-(D-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-methionine 2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-phenyl- propionyl-methionine sulfone methyl ester 2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-ρhenyl- propionyl-methionine sulfone N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-methyl- enedioxybenzyl)glycyl-methionine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3- methylenedioxybenzyl)glycyl-methionine N-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N-(2,3- dihydrobenzofuran-7-ylmethyl)glycyl-methionine methyl ester N-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N-(2,3- dihydrobenzofuran-7-ylmethyl)glycyl-methionine N-{2(S)-[3-(3-indolyl)proρionyl]amino-3(S)-methylpentyl}-N-(l- naphthylmethyl)glycyl-methionine methyl ester N-{ 2(S)-[3-(3-indolyl)propionyl]amino-3(S)-methylpentyl }-N-(l- naphthylmethyl)glycyl-methionine N- { 2(S)- [3-( 1 -indolyl)proρionyl] amino-3 (S)-methylpentyl } -N-( 1 - naphthylmethyl)glycyl-methionine methyl ester N-{2(S)-[3-(l-indolyl)ρropionyl]amino-3(S)-methylρentyl}-N-(l- naphthylmethyl)glycyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-histidine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-( 1 -naphthyl- methyl)glycyl-histidine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(cyclo- propylmethyl)glycyl-methionine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine N-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine methyl ester N-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3- dihydrobenzofuran-7-ylmethyl)glycyl-methionine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3- dihydrobenzofuran-7-ylmethyl)glycyl-methionine 2(S)-[2(S)-N-(L-Pyroglutamyl)-N-methylamino-3(S)-methylpentyloxy]- 3-phenylpropionyl-methionine methyl ester 2(S)-[2(S)-N-(L-Pyroglutamyl)-N-methylamino-3(S)-methylpentyloxy]- 3-phenylpropionyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-0-methylserine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-( 1 - naphthylmethyl)glycyl-0-methylseιine N-(l-Naphthylmethyl)-N-[2(S)-(N'-(L-ρyroglutamyl)-N'-methylamino)- 3(S)-methylpentyl]-glycyl-methionine methyl ester N-(l-Naphthylmethyl)-N-[2(S)-(N'-(L-pyroglutamyl)-N'-methylamino)- 3(S)-methylpentyl]-glycyl-methionine N- [ 1 -(Pyroglutamylamino)cyclopent- 1 -ylmethyl]-N-( 1 -naphthylmethyl)- glycyl-methionine methyl ester N-[ 1 -(Pyroglutamylamino)-cyclopent- 1 -ylmethyl]-N-( 1 -naphthylmethyl)- glycyl-methionine N-[2(S)-(Pyridin-2-on-6-ylcarbonyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-methionine methyl ester N-[2(S)-(Pyridin-2-on-6-ylcarbonyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(3-chloro- benzyl)glycyl-methionine methyl ester N- [2(S)-(L-ρyroglutamyl)amino-3 (S)-methylpentyl]-N-(3-chloro- benzyl)glycyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-0-methylhomoseιine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-0-methylhomoserine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-dimethyl- benzyl)glycyl-methionine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-dimethyl- benzyl)glycyl-methionine N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-(2-thienyl)alanine methyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(l-naphthyl- methyl)glycyl-(2-thienyl)alanine N-[2(S)-(pyrrolidin-2-on-l-yl)-3-methylbutanoyl]-isoleucyl-methionine; N-[2(S)-(piρeridin-2-on-l-yl)-3-methylbutanoyl]-isoleucyl-methionine; or the pharmaceutically acceptable salts thereof. The composition of the instant invention may alternatively comprise a farnesyl pyrophosphate-competitive farnesyl-protein transferase inhibitor. Thus the following compounds, well known in the art, are useful as farnesyl pyrophosphate-competitive inhibitors in the instant invention: bb) U.S.Pat. No. 5, 260,465, incorporated herein by reference, wherein: X - X is: CH = CH (cis); CH = CH (trans); or CH2CH2; Rl and R2 are each independently selected from: a) H; b) Cl-5 alkyl; c) Cl-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula (I) in which at least one of Rl and R2 is hydrogen; cc) U.S.Pat. No. 5, 420,157, incorporated herein by reference, wherein: Rl and R2 are each independently selected from: a) H; b) Cl-5 alkyl; c) Cl-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula (I) in which at least one of Rl and R2 is hydrogen; dd) U.S.Pat. Nos. 5, 245,061 and 5, 350,867, incorporated herein by reference, wherein: X - X is: CH = CH (cis); CH = CH (trans); or CH2CH2; Rl and R2 are each independently selected from: a) H; b) Cl-5 alkyl; c) Cl-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula (I) in which at least one of Rl and R2 is hydrogen; ee) US. Serial No. 08/ (Case 19265, filed June 2, 1995); incorporated herein by reference; I or the pharmaceutically acceptable salts, hydrates, esters or amides thereof, wherein: n is: 0 to 4, Rl and R independently are Cθ-4 alkyl, substituted with substituents selected from the group consisting of: a) aryl, which is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of: i) F, π) Cl, iii) Br, iv) nitro, v) cyano, vi) Cl-8 alkoxy, vii) Cl-8 alkylthio, viii) Cl-8 alkylsulfonyl, ix) sulfamoyl, or x) Cl-8 alkyl; or b) heteroaryl, which is defined as indolyl, imidazolyl or pyridyl, unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of: i) F, ϋ) Cl, iii) Br, iv) nitro, v) cyano, vi) Cl-8 alkoxy, vii) Cl-8 alkylthio, viii) Cl-8 alkylsulfonyl, ix) sulfamoyl, or x) Cl-8 alkyl; R is: Cθ-6 alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: a) unsubstituted or substituted aryl, as defined in Rl(a), b) unsubstituted or substituted heteroaryl, as defined in Rl(b), c) C3-8 cycloalkyl, d) Cl-8 alkylthio, e) Cl-8 alkylsulfonyl, f) Cl-8 alkoxy, or g) aryl Cl-8 alkyl sulfonyl; and R4 is: H; ff) U.S. Pat. Nos. 5,298,655 and 5,362,906; incorporated herein by reference; wherein: X is CH2, CH(OH), C=0, CHCOR, CH(NH2), CH(NHCOR), O, S(0) p , NH, NHCO, 0 II 9 II - CNH -, - NH - P - ; OH p is 0, 1 or 2; Y is PO3RR 1 or C02R; R is H, lower alkyl, or CH2CH 2 N+Me3A-; Rl is H, lower alkyl, or CH2CH2N+Me3A-, A is a pharmaceutically acceptable anion; m is 0, 1, 2, or 3; and n is O, 1, 2, or 3; or the pharmaceutically acceptable salts thereof. Specific examples of farnesyl pyrophosphate-competitive inhibitors include: 3-Hydroxy-7,l l,15-trimethylhexadeca-6,10,14-trienoic acid, [2- Oxo-6,10,14-trimethylpentadeca-5,9,13-trienyl]phosphonic acid [2- Hydoxy-6, 10,14-trimethylpentadeca-5,9, 13-trienyl]phosphonic acid [1- Acetyl-4,8,12-trimethylρentadeca-3,7,l l-trienyl]phosphonic acid [2- [(E,E)-3,7, 11 -Trimethyl-2,6, 10-dodecatrienylamino]-2-oxo- ethyl]phosphonic acid [(E,E)-4,8,12-Trimethyl-3,7,l l-tridecatrienyl]thiomethyl-phosphonic acid 3-[(E,E)-3,7,l l-Trimethyl-2,6,10-dodecatrienylamino]-3-oxo-propionic acid [2-[(E,E)-3,7,ll-Trimethyl-2,6,10-dodecatrienylamino]-2-oxo- ethyl]ρhosphonic acid monomethyl ester [2- [(E,E)-3 ,7, 11 -Trimethyl-2,6, 10-dodecatrienylamino] - 1 -oxo- methyljphosphonic acid [ 1 -Hydroxy-(E,E)-3 ,7 , 11 -trimethy 1-2,6, 10-dodecatrienyl]-phosphonic acid [l-Hydroxy-(E,E)-5,9,13-trimethyl-4,8,12-tetradecatrienyl]-phosphonic acid [l-Hydroxy-(E,E)-4,8,12-trimethyl-3,7,l l-tridecatrienyl]-phosphonic acid [2-Acetamido-(E,E)-4,8,12-trimethyl-3,7,l l-tridecatrienyl]-phosphonic acid and [2-Hydroxy-(E,E)-4,8,12-trimethyl-3,7,l l-tridecatrienyl]-phosphonic acid or a pharmaceutically acceptable salt. The composition of the instant invention may alternatively a farnesyl pyrophosphate-competitive inhibitor obtained by fermentation of cultures of novel organisms. In particular, the compounds disclosed in the following patent may be useful as a farnesyl pyrophosphate- competitive inhibitor component of the instant composition: U.S. Ser. Nos. 08/ 254,228. That patent is incorporated herein by reference. In addition, compounds described in the following patents and publications may also be utilized as a farnesyl pyrophosphate- competitive inhibitor component of the instant composition: European Pat. Publ. 0 537 008; European Pat. Publ. 0 540 782; PCT Pat. Publs. WO 94/1935; WO 95/12572 ; and WO 95/08546. Those patents and publications are incorporated herein by reference. The protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. Unless otherwise specified, named amino acids are understood to have the natural "L" stereoconfiguration As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. As used herein, "cycloalkyl" is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. "Alkenyr' groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like. As used herein, "aryl" is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like. The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro- benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamoφholinyl, thiamoφholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl)2, Nθ2, CN, ( -C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0)m-, (C1-C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(0)NH- and C1-C20 alkyl. The following structure: represents a cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring. Examples of such a cyclic amine moiety include, but are not limited to, the following specific structures: It is also understood that substitution on the cyclic amine moiety by R2a, R2b, R7a and R7b may be on different carbon atoms or on the same carbon atom. When R2 and R2b,and R3 and R4 are combined to form - (CH2)s -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: When R^a and R^b are combined to form - (CH2)s -, cyclic moieties as described hereinabove for R and R4 are formed. In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: COR 10 As used herein, the phrase "nitrogen containing C4-C9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be a C6 aromatic ring, a C5-C7 saturated ring or a heterocycle" which defines moiety "Q" of the instant invention includes but is not limited to the following ring systems: It is intended that the definition of any substituent or variable (e.g., RlO, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(RlO)2 represents -NHH, -NHCH3, -NHC 2 H5, etc. It is understood that substituents and substitution patterns on the protein substrate- competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below. The pharmaceutically acceptable salts of the protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. The pharmaceutically acceptable salts of the protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors of this invention can be synthesized from the corresponding inhibitor of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Some of the protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al, "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al, "Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 1980, or Stewart et al., "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. Also useful in exemplifying syntheses of specific unnatural amino acid residues are European Pat. Appl. No. 0 350 163 A2 (particularly page 51-52) and J. E. Baldwin et al. Tetrahedron, 50:5049-5066 (1994). With regards to the synthesis of instant compounds containing a (β-acetylamino)alanine residue at the C- terminus, use of the commercially available N«-Z-L-2,3- diaminopropionic acid (Fluka) as a starting material is preferred. The teachings of these works are hereby incoφorated by reference. Abbreviations used in the description of the chemistry and in the Examples that follow are: The protein substrate-competitive inhibitors of this invention designated "v)" hereinabove are prepared by employing the reactions shown in the following Reaction Schemes A-R, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Such Reaction Schemes are also useful in preparing other protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhbitors. For example, Reaction Schemes A-E are especially useful in preparing the inhibitors designated "a)" through "k)", "m) M , "n)", "q)" through "u)" and "ee)" hereinabove. Some key bond-forming and peptide modifying reactions are: Reaction A Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies. Reaction B Preparation of a reduced peptide subunit by 1 reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents. Reaction C Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents. Reaction D Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies. Reaction E Preparation of a reduced subunit by borane reduction of the amide moiety. Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incoφorating acyclic peptide units. It is well understood that such reactions are equally useful when the - NHC(RA) - moiety of the reagents and compounds illustrated is replaced with the following moiety: These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes. REACΗON SCHEME A Reaction A. Coupling of residues to form an amide bond REACTION SCHEME B Reaction B. Preparation of reduced peptide subunits by reductive alkylation I O R A R B θΛN H + H . N - REACTION SCHEME C Reaction C. Alkylation/reductive alkylation of reduced peptide subunits R y CH, NaCNBH, R fc REACTION SCHEME D Reaction D. Coupling of residues to form an amide bond R A H N y REACΗON SCHEME E Reaction E. Preparation of reduced dipeptides from peptides where RA and RB are R3, R4, R5a or R5b as previously defined; RC is R6 as previously defined or a carboxylic acid protecting group; XL is a leaving group, e.g., Br-, I- or MsO-; and Ry is defined such that R7b is generated by the reductive alkylation process. Certain compounds of this invention wherein X-Y is an ethenylene or ethylene unit are prepared by employing the reaction sequences shown in Reaction Schemes F and G. Reaction Scheme F outlines the preparation of the alkene isosteres utilizing standard manipulations such as Weinreb amide formation, Grignard reaction, acetylation, ozonolysis, Wittig reaction, ester hydrolysis, peptide coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or exemplified in the Experimental Procedure. For simplicity, substituents R2a and R2b on the cyclic amine moiety are not shown. It is, however, understood that the reactions illustrated are also applicable to appropriately substituted cyclic amine compounds. The key reactions are: stereoselective reduction of the Boc-amino-enone to the corresponding syn amino-alcohol (Scheme F, Step B, Part 1), and stereospecific boron triflouride or zinc chloride activated organo- magnesio, organo-lithio, or organo-zinc copper(l) cyanide SN2' displacement reaction (Scheme F, Step G). Through the use of optically pure N-Boc amino acids as starting material and these two key reactions, the stereo-chemistry of the final products is well defined. In Step H of Scheme F, the amino terminus sidechain, designated Rx is incoφorated using coupling reaction A and RxCOOH; the alkylation reaction C using RxCHO and a reducing agent; or alkylation reaction C using RXCH2XL. Such reactions as described in Step H are described in more detail in Reaction Schemes J-X hereinbelow. The alkane analogs are prepared in a similar manner by including an additional catalytic hydrogenation step as outlined in Reaction Scheme G. REACTION SCHEME F Step A REACTION SCHEME F (CONT'D ^ ) wherein R χ (CR 1b 2 ) p REACTION SCHEME F fCQNT'D^ NaOH 1.HCI Alternate StepH O II 2. R x COH EDC, HOBT REACTION SCHEME G MsCI, py REACTION SCHEME G (CONT'D 1. R 3 MgCuCNCI-BF 3 2. H 2 , 5% Pd/C NaOH REACTION SCHEME G (CONT'D) or o 1. HCI 2. R x COH EDC, HOBT NaOH The oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H. An aminoalcohol 1 is acylated with alpha-chloroacetyl chloride in the presence of trialkylamines to yield amide 2. Subsequent reaction of 2 with a deprotonation reagent (e.g., sodium hydride or potassium t-butoxide) in an ethereal solvent such as THF provides moφholinone 3. Alkylation of 3 with R3χL, where XL is a leaving group such as Br-, I- or Cl- in THF/DME (1,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], affords 4, which is retreated with NaHMDS followed by either protonation or the addition of an alkyl halide R4χ to give 5a or 5b, respectively, as a enantiomeric mixture. Alternatively, 5a can be prepared from 3 via an aldol condensation approach. Namely, deprotonation of 3 with NaHMDS followed by the addition of a carbonyl compound RYRzCO gives the adduct 6. Dehydration of 6 can be effected by mesylation and subsequent elimination catalyzed by DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) or the direct treatment of 6 with phosphorus oxychloride in pyridine to give olefin 7. Then, catalytic hydrogenation of 7 yields 5a (wherein -CHRYR 2 constitutes R3). Direct hydrolysis of 5 with lithium hydrogen peroxide in aqueous THF, or aqueous HC1, produces acid 8a. Compound 8a is then derivatized with BOC-ON or BOC anhydride to give 8b. The peptide coupling of acid 8b with either an alpha-aminolactone (e.g., homoserine lactone, etc.) or the ester of an amino acid is carried out under the conditions exemplified in the previously described references to yield derivative 9. Treatment of 9 with gaseous hydrogen chloride gives 10, which undergoes further elaboration as described in Reaction Schemes J- hereinbelow. An alternative method for the preparation of the prolyl oxa isostere (compounds 23 and 24 ) is shown in Scheme H- 1. Referring to Scheme H-l, the aminoalcohol 1 is protected with trifluoroacetic anhydride and the blocked compound 15 treated with diphenyl disulfide in the presence of tributylphosphine to provide the thioether 16. Chlorination of compound 16 provides compound 17 which can be reacted with the appropriate carboxylic acid alcohol in the presence of silver perchlorate and tin (II) chloride, to afford the mixed acetal 18. Removal of the phenylmercapto moiety with Raney nickel provides compound 19. Compound J_9 is doubly deprotected, then selectively BOC protected to provide the acid 20, which undergoes the steps previously described for incoφorating terminal amino acid. Still another alternative method for the preparation of the prolyl oxa isostere (compounds 23 and 24 ) is described in the literature [Ruth E. TenBrink, J. Org. Chem., 52, 418-422 (1987)]. SCHEME H SCHEME H (CONT'D) a, R w = H b, R w = BOC SCHEMEH-1 SCHEME H-1 (CONT'D) The thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I. Aminoalcohol 1 is derivatized with BOC2O to give 25. Mesylation of 25 followed by reaction with methyl alpha-mercaptoacetate in the presence of cesium carbonate gives sulfide 26. Removal of the BOC group in 26 with TFA followed by neutralization with di-isopropylethylamine leads to lactam 27. Sequential alkylation of 27 with the alkyl halides R3χ and R4χ in THF/DME using NaHDMS as the deprotonation reagent produces 28. Hydrolysis of 28 in hydro-chloride to yield 29a, which is derivatized with Boc anhydride to yield 29b. The coupling of 29b with an alpha-aminolactone (e.g., homoserine lactone, etc.) or the ester of an amino acid is carried out under conventional conditions as exempHfied in the previously described references to afford 30. Sulfide 30 is readily oxidized to sulfone 31 by the use of MCPB A (m-chloroperoxybenzoic acid). The N-BOC group of either 30 or 31 is readily removed by treatment with gaseous hydrogen chloride. SCHEMEI SCHEME I (CONT'D) m=0, 30 MCPBA m=2, 31 32 m = 0 or 2 Reaction Schemes J - R illustrate reactions wherein the non- sulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to the fully elaborated cyclic amino peptide unit, prepared as described in Reaction Schemes A-I. It is understood that the reactions illustrated may also be performed on a simple cyclic amino acid, which may then be further elaborated utilizing reactions described in Reaction Schemes A- 1 to provide the instant compounds. The intermediates whose synthesis are illustrated in Reaction Schemes A-I can be reductively alkylated with a variety of aldehydes, such as V, as shown in Reaction Scheme J. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme F). The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product VI can be deprotected with trifluoroacetic acid in methylene chloride to give the final compounds VII. The final product VII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine VII can further be selectively protected to obtain VHI, which can subsequently be reductively alkylated with a second aldehyde to obtain IX. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XI can be accomplished by literature procedures. Alternatively, the protected cyclic aminopeptidyl intermediate can be reductively alkylated with other aldehydes such as 1- trityl-4-carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as XII (Reaction Scheme K). The trityl protecting group can be removed from XII to give XIII, or alternatively, XII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XIV. Alternatively, the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques. The imidazole acetic acid XV can be converted to the protected acetate XVII by standard procedures, and XVII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XVIII. Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the presence of condensing reagents such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XIX. If the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XX in Reaction Scheme N, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes N, P). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIV. In addition, the fully deprotected amino alcohol XXV can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXVI (Reaction Scheme P), or tertiary amines. The Boc protected amino alcohol XXII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXVII (Reaction Scheme Q). Treating XXII with l,l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXVΗ . The aziridine may be reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXVIII . In addition, the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIV, as shown in Reaction Scheme R. When R' is an aryl group, XXXIV can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXV. Alternatively, the amine protecting group in XXXIV can be removed, and O-alkylated phenolic amines such as XXXVI produced. REACTIQN SCHEME J wherein REACTION SCHEME J (continued) REACTION SCHEME K XII 1) Ar CH 2 X, CH 3 CN 2) CF 3 C0 2 H, CH 2 CI 2 (C 2 H 5 ) 3 SiH CF 3 C0 2 H, CH 2 CI (C 2 H 5 ) 3 SiH XIII REACTION SCHEME L XV XVI 1) ArCH 2 X CH 3 CN reflux 2) CH 3 OH, reflux XVII XVIII REACTION SCHEME M REACTION SCHEME N XX REACTION SCHEME N (CONΗNUED) . REACTION SCHEME P REACΗON SCHEME O REACTION SCHEME R XXIX XXX XXXI XXXII XXXIII REACTION SCHEME R (continued) BocNH CHO « XXXIII Reactions used to generate the inhibitors of this invention which are designated "y)" are shown in the Reaction Schemes 1-16, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R a and Rb, as shown in the Schemes, represent the substituents R2, R3, R4 ? ^d R5; however their point of attachment to the ring is illustrative only and is not meant to be limiting. These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes. Reaction Schemes 1-16 are also useful in preparing inhibitors of this invention that are designated "1)". Synopsis of reaction Schemes 1-16: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. In Scheme 1, for example, the synthesis of 2-alkyl substituted piperazines is outlined, and is essentially that described by J. S. Kiely and S. R. Priebe in Organic Preparations and Proceedings Int.. 1990, 22, 761- 768. Boc-protected amino acids I, available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDCΗCl (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethylformamide. The product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III. Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected as the Boc derivative V. The N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10% palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h. The product VI can be treated with an acid chloride, or a carboxylic acid under standard dehydrating conditions to furnish the carboxamides VII; a final acid deprotection as previously described gives the intermediate VIII (Scheme 2). The intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Scheme 3). The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride. The final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures. Alternatively, the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as l-trityl-4- carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme IV). The trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII. Alternatively, the intermediate VIII can be acylated or sulfonylated by standard techniques. The imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII. Hydrolysis and reaction with piperazine VIII in the presence of condensing reagents such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) leads to acylated products such as XXIV. If the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 7). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX. In addition, the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines. The Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8). Treating XXVII with l,l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIII. In addition, the piperazine VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIX. When R' is an aryl group, XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL. Alternatively, the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced. Depending on the identity of the amino acid I, various side chains can be incorporated into the piperazine. For example when I is the Boc-protected β-benzyl ester of aspartic acid, the intermediate diketopiperazine XLII where n=l and R=benzyl is obtained, as shown in Scheme 10. Subsequent lithium aluminum hydride reduction reduces the ester to the alcohol XLIII, which can then be reacted with a variety of alkylating agents such as an alkyl iodide, under basic conditions, for example, sodium hydride in dimethylformamide or tetrahydrofuran. The resulting ether XLIV can then be carried on to final products as described in Schemes 3-9. N-Aryl piperazines can be prepared as described in Scheme 11. An aryl amine XLV is reacted with bis -chloroethyl amine hydrochloride (XLVI) in refluxing n -butanol to furnish compounds XL VII. The resulting piperazines XL VII can then be carried on to final products as described in Schemes 3-9. Piperazin-5-ones can be prepared as shown in Scheme 12. Reductive amination of Boc-protected amino aldehydes XLIX (prepared from I as described previously) gives rise to compound L. This is then reacted with bromoacetyl bromide under Schotten-Baumann conditions; ring closure is effected with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide to give LI. The carbamate protecting group is removed under acidic conditions such as trifluoroacetic acid in methylene chloride, or hydrogen chloride gas in methanol or ethyl acetate, and the resulting piperazine can then be carried on to final products as described in Schemes 3-9. The isomeric piperazin-3-ones can be prepared as described in Scheme 13. The imine formed from arylcarboxamides LII and 2- aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine LIV. Amino acids I can be coupled to amines LIV under standard conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated LVI. Catalytic hydrogenation under standard conditions gives the requisite intermediate LVII, which is elaborated to final products as described in Schemes 3-9. Access to alternatively substituted piperazines is described in Scheme 14. Following deprotection with trifluoroacetic acid, the N-benzyl piperazine V can be acylated with an aryl carboxylic acid. The resulting N-benzyl aryl carboxamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxamide LX which can then be carried on to final products as described in Schemes 3- 9. Reaction Scheme 15 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents R2 and R3 are combined to form - (CH2)u -• For example, 1- aminocyclohexane-1 -carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2. The piperazine intermediate LXD can be deprotected as before, and carried on to final products as described in Schemes 3-9. It is understood that reagents utilized to provide the substituent Y which is 2-(naphthyl) and the imidazolylalkyl substituent may be readily replaced by other reagents well known in the art and readily available to provide other N-substituents on the piperazine. The aldehyde XLIX from Scheme 12 can also be reductively alkylated with an aniline as shown in Scheme 16. The product LXXI can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base-induced cyclization to LXXIII. Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXV, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXXVI. Final removal of protecting groups by either solvolysis with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane in methylene chloride in the presence of trifluoroacetic acid gives the final product LXXVII. SCHEME 1 II III IV SCHEME 2 HCI, EtOAc VII SCHEME 3 XI XII SCHEME 3 (continued) SCHEME 4 SCHEME 5 XIX XX XXI XXII SCHEME 5 (continued) XXIII XXIV SCHEME 6 XXV XXVI XXVII SCHEME 6 (CONTINUED) XXVIII SCHEME 7 XXVII XXX SCHEME 8 XXVII XXXII XXXIII SCHEME 9 XXXIV XXXV XXXVI XXXVII XXXVIII SCHEME 9 (continued) XXXVIII XL SCHEME 10 XLIII SCHEME11 ArNHo + XLV XLVI n - butanol reflux XLVII SCHEME 12 XLVII I pH6 XLIX H 2) NaH, THF, DMF L SCHEME 12 (CONT'D) Ll r SCHEME 13 ArCHO + NH 2 CH 2 CH(OC 2 H 5 ) 2 NaBH(OAc) 3 LIV EDC . HCI, HOBT DMF, Et 3 N, pH 7 LV LVI SCHEME 14 LVI 11 SCHEME 15 LXI - LiAIH < HN' N- \ / THF O SCHEME 15 (continued) LXX SCHEME 16 BocNH CICH 2 CH 2 CI XLIX LXXI R Cl Cl BocNH N-Ar EtOAc / H 2 0 NaHC0 3 Cl o LXXI I R NaH / — \ HCI BocN N-Ar DMF V. i EtOAc O LXXIII SCHEME 16 (continued) LXXV LXXVI LXXVI I The compositions of this invention inhibit Ras farnesyl transferase which catalyzes the first step in the post-translational processing of Ras and the biosynthesis of functional Ras protein. These compositions are useful as pharmaceutical agents for mammals, especially for humans. These compositions may be administered to patients for use in the treatment of benign proliferative disorder neurofibromatosis and symptoms associated with neurofibromatosis such as benign neurofibromas, optic gliomas, pseudoarthoses and learning disabilities. The compositions may also be administered to young mammals who are genetically disposed to NFl prior to the manifestation of the disease, thereby preventing the disease or lessening its effects. In practicing the methods of this invention, which comprise administering a composition comprising a farnesyl-protein transferase inhibitor, such administration can be orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. It is preferred that such administration be orally. It is more preferred that such administration be orally and simultaneously. The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. For oral use of an anti-benign proliferative disorder neurofibromatosis composition according to this invention, the selected composition may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection. When a composition according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. In one exemplary application, a suitable amount of composition is administered to a mammal undergoing treatment for benign proliferative disorder neurofibromatosis. Administration occurs in an amount of a composition that comprises between about 0.1 mg/kg of body weight to about 40 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 20 mg/kg of body weight per day of a farnesyl-protein transferase inhibitor. EXAMPLES Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof. EXAMPLE 1 In vitro inhibition of ras farnesyl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) is prepared as described by Schaber et al, J. Biol Chem. 265: 14701-14704 (1990), Pompliano, et al, Biochemistry 3 :3800 (1992) and Gibbs et al, PNAS U.S.A. 56:6630-6634 (1989), respectively. Bovine FPTase is assayed in a volume of 100 μl containing 100 mM Λ 7 -(2-hydroxy ethyl) piperazine-TV- (2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at 31°C for 60 min. Reactions are initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates are collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB β-plate counter. The assay is linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP is utilized during the reaction period. Individual purified protein substrate-competitive inhibitor and/or farnesyl pyrophosphate-competitive inhibitor and compositions of the invention that comprise at least one of a protein substrate-competitive inhibitor and a farnesyl pyrophosphate-competitive inhibitor are dissolved in 100% dimethyl sulfoxide (DMSO) and are diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound. Human FPTase is prepared as described by Omer et al, Biochemistry 32:5167-5176 (1993). Human FPTase activity is assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 μM ZnCl 2 and 100 nM Ras-CVIM are added to the reaction mixture. Reactions are performed for 30 min., stopped with 100 μl of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme. Comparison is made between the inhibitory activity of a composition of the instant invention and the inhibitory activities of individual compounds that make up the composition in the assay. EXAMPLE 2 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al, Cancer Research 51:112-111, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain 0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al, J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4°C, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein. Comparison is made between the inhibitory activity of a composition of the instant invention and the inhibitory activities of individual compounds that make up the composition in the assay. EXAMPLE 3 Effect of Compound A on NFl Schwann cells: Wild type and homozygous mutant mouse Schwann cells were isolated from E12.5 NFl mouse embryos and plated at 25,000 cells per well on a poly-L-lysine coated 8 well glass Lab-Tek slide in DMEMmedia containing 10% FBS. Various concentrations of Compound A were added to the culture medium and the cultures preincubated for two days. After the preincubation the culture medium was changed to a serum-free medium supplemented with glial growth factor. The following day, [3H]-thymidine (4 μCi ml) was added to the culture and after 16-18 hours of labeling period, cells were fixed and processed for autoradiography and immunostaining for nerve growth factor receptor (NGFR). Schwann cell DNA synthesis was determined by counting the percentage of labeled nuclei of NGFR positive cells. The results are shown in Figure 1. EXAMPLE 4 Effect of Forskolin on NFl Schwann cells: Wild type and homozygous mutant mouse Schwann cells were isolated from E12.5 NFl mouse embryos and plated at 25,000 cells per well on a poly-L-lysine coated 8 well glass Lab-Tek slide in DMEMmedia containing 10% FBS. After the preincubation the culture medium was changed to a serum-free medium supplemented with various concentrations of forskolin. The following day, [^HJ-thymidine (4 μCi/ml) was added to the culture and after 16-18 hours of labeling period, cells were fixed and processed for autoradiography and immunostaining for NGFR. Schwann cell DNA synthesis was determined by counting the percentage of labeled nuclei of NGFR positive cells. The results are shown in Figure 2. EXAMPLE 5 Effect of Compound A on Forskolin mediated NFl Schwann cell growth: Homozygous mutant mouse Schwann cells were isolated from E12.5 NFl mouse embryos and plated at 25,000 cells per well on a poly-L-lysine coated 8 well glass Lab-Tek slide in DMEM media containing 10% FBS. Various concentrations of Compound A were added to the culture medium and the cultures preincubated for two days. After the preincubation the culture medium was changed to a serum-free medium supplemented with 2μM of forskolin. The following day, [3H]- thymidine (4 μCi/ml) was added to the culture and after 16-18 hours of labeling period, cells were fixed and processed for autoradiography and immunostaining for NGFR. Schwann cell DNA synthesis was determined by counting the percentage of labeled nuclei of NGFR positive cells. The results are shown in Figure 3.

Claims: WHAT IS CLAIMED IS: 1. A method for treating benign proliferative disorder neurofibromatosis in a mammal in need thereof which comprises administering to said mammal a pharmaceutically effective amount of a compound that inhibits farnesyl-protein transferase. 2. The method according to Claim 1 wherein the compound that inhibits farnesyl-protein transferase is Compound A: or a pharmaceutically acceptable salt thereof. 3. A method for preventing benign proliferative disorder neurofibromatosis in a mammal in need thereof which comprises administering to said mammal a pharmaceutically effective amount of a compound that inhibits farnesyl-protein transferase. 4. The method according to Claim 3 wherein the compound that inhibits farnesyl-protein transferase is Compound A: or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition for achieving an therapeutic effect against benign proliferative disorder neurofibromatosis in a mammal in need thereof which comprises a pharmaceutically effective amount of a compound that inhibits farnesyl-protein transferase. 6. The composition according to Claim 3 wherein the compound that inhibits farnesyl-protein transferase is Compound A: or a pharmaceutically acceptable salt thereof.

Inventors: RATNER NANCY, RATNER, NANCY
Applicants: RATNER NANCY, UNIV CINCINNATI, RATNER, NANCY, UNIVERSITY OF CINCINNATI
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P25, A61P35, A61P43