CYSTEINYL PROTEASE INHIBITORS

Abstract: Amino acid di- and tri-peptide analogs having C-terminal vinylic groups, pharmaceutical compositions containing the analogs and methods of treating diseases using cysteinyl protease inhibitors; particularly neurodegenerative, autoimmune, cognitive disorders, stroke and traumatic injury.

Description: CYSTEINYL PROTEASE INHIBITORS FIELD OF THE INVENTION The invention relates to protease inhibitor compounds useful in treatments of neurodegenerative, cardiovascular, pulmonary, neuromuscular, musculovascular and autoimmune diseases characterized by tissue damage, induction of apoptosis, cell death and or the accumulation of amyloid proteins in deposits, plaques, fibrils*and tangles. BACKGROUND OF INVENTION Cysteinyl proteases are implicated in important cellular processes including endocytosis and degradation of proteins, immune recognition, apoptosis and processing of amyloid precursor protein. Cysteinyl proteases are localized in the endosomal lysosomal compartment, possibly the endoplasmic reticulum and cytosol. While many of the molecular details are at present uncertain, the importance of cysteinyl proteases at the cellular level and at an organism level cannot be overstated. In Alzheimer's disease (AD), amyloid precursor protein (APP; i.e., APP 695 ) is proteolytically processed in neural cells and Aβ cleavage fragments are secreted into cerebral extracellular perivascular matix. Plaques containing Aβ act as a pathological landmark of AD (2-5) and in vitro studies have shown to that Aβ can aggregate into insoluble fibrils which ultrastructurally resemble amyloid plaques (7). Aggregated in a Fibrillar beta-pleated sheet configuration, Aβ is thought to form a nidus for binding other proteins contributing to Alzheimer's dementia and pathology. Aβ fibrils are reportedly toxic for cultured neurons in vitro (8), possibly through induction of apoptosis (9), initiation of free radical formation (10) or increases in peroxide (H 2 0 2 ) levels in cells (1 1). APP, synthesized by neuronal cells, full length APP may be degraded in lysosomes (21,22), resulting in noπ-amyloidogenic fragments, or it can be proteolytically processed to polypeptides of l lOkDa, i.e., sAPP ( 16- 17); 9-10kDa ( 17); and 4.2kDa, i.e., Aβ ( 18- 19). Characterization of fragments and protease inhibitor profiles suggest three intracellular enzymes, termed secretases, differing as follows: namely, Alpha-secretase (α-secretase) mediates cleavage of APP 695 and APP 751 producing sAPP (l lOkDa) and a 9-10kDa carboxy-terminal-fragment (CTF; i.e., APP6i ι^95)- The CTF fragment may undergo further degradation in lysosomes (17). Products of lysosomal and α-secretase cleavages are generally considered to be non- amyloidogenic; Beta-secretase (β-secretase) mediates cleavage of AP 95 in the carboxy- termina! region (i.e., at APP Met 5 5-Asp596; Aβ Aspi; 23), producing a 1 1.4- 1 1.8kDa fragment, 100 amino acids in length (CTF100), and containing the Aβ domain; and, Gamma-secretase (γ-secretase) mediates cleavage in the C-terminal transmembrane domain of APP (i.e., APP G62 4 AϋGLMVGGVVIA637), and possibly also CTFIOO, to release the Aβι.39, Aβj-rø and or Aβι-42 peptides. Both and being more active than Aβ 40 (7,24,25). Sensitivity of secretases to protease inhibitors has been studied in cell-based assays, i.e., by treating APP producer cells with protease inhibitors. Results have varied in different cells and under differing conditions of culture. In certain reports, APP cleavage is reportedly inhibited by serine protease inhibitors; in others by inhibitors of chymotrypsin-like enzymes; and in others by inhibitors of cysteinyl proteases such as cathepsins B, D, H, L and S and calpain. Studies with leupeptin (26,27), E64 and Z-Phe-Ala-CHN∑ (28), i.e., lysosomal enzyme inhibitors, have failed to implicate known lysosomal hydrolases in production of Aβ. Similarly, although calpain inhibitor L, a caspase inhibitor, was initially reported effective in reducing Aβ levels m vitro (29), subsequent findings seem at odds with an effect on a putative γ-secretase (30) Dipeptidyl-aldehyde inhibitor, Z-L-Val-L D-Phe-aldehyde (MDL 28170) and AEBSF [4-(2-amιnoethyl)-benzene lfonyl fluoride hydrochloride] were also once thought to inhibit Aβj_ 2 production (32) Since nonspecific acidotropic agents such as NH-jCI and chloroquine, or Golgi inhibitors such as brefeldin A and monensin ( 19,27), reportedly affect APP processing it is possible that it takes place in the endoplasmic -"ticulum (ER) and or Golgi apparatus Specific and targeted inhibitors of secretase enzymes have (to date) proven elusive In apoptosis, an intracellular cascade of cysteinyl proteases, termed caspases, is activated b> radiation damage to cellular DNA or structures (e.g., mitochondπa), or by removal of one or more critical growth factors (e. , EGF, PGF, TGFβ, NGF, BDNF), glucose or serum In addition, a vaπety of different receptor hgand interactions at the cell surface may tπgger apoptosis in vitro e g , anti-Fas antibody or Fas hgand binding to Fas receptor, EL- 1 binding to IL-l Rβ, TNFα binding to TNFR1 and TNFR2, Apo 3 hgand binding to Death Receptor 3, glucocorticoids binding to cell surface glycocorticoid receptors, TRAIL, TRANCE and NOC18 binding to yet other cell surface "death' receptors Important cysteinyl proteases activated in this manner are thought to include caspases 3, 8 and 9 Apoptosis has recentK been implicated in mechanisms by which tissue damage is triggered following traumatic injury, vascular insufficiency and stroke Using knockout mice, Cathepsin S is reportedly involved in class I MHC antigen processing, I e , of self and viral antigens, while Cathepsin L is involved in class D processing of foreign proteins Thus, protease inhibitors find a vaπety of important medical and veteπnary uses in treatments of diseases, as well as, uses in the food, dairy, agπculture, chemical and biotechnology industπes SUMMARY OF THE INVL i lON Cysteinyl protease inhibitors, pharmaceutical compositions and methods of treating protein processing disorders, trauma, stroke, autoimmunity, neurodegenerative and cognitive disorders including Alzheimer's disease, are disclosed The di- and iπ-peplide analogues with unnatural α-amino side chain residues and deπvatized ammo and carboxyl terminal residues constitute highly effective inhibitors of cysteinyl proteases including e g cathepsins, caspases, calpains and secretases Methods and pharmaceutical compositions are provided for modulating activities of cysteinyl proteases involved in diseases including methods for alteπng secretase-mediated processing of APP in Alzheimer's disease and aberrant cathepsin S-mediated processing of self proteins for MHC class I presentation in autoimmune diseases The instant compounds include vinyl sulfides, sulfoxides, sulfones, amines, amine oxides, phosphines, phosphine oxides, phosphinates and phosphonates of peptιd) l analogs of di- and tπ-peptides, where the vinyl substituent in the peptidyl analog preferably occupies the carboxyl-terminal position and consists of a substituted alkenyl or alkynyl side chain DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments of the invention provide cysteinyl protease inhibitors The instant compounds are vinyl heterocyclic alkyls and aryl adducts of peptidyl analogs of natural α-amino acid containing cysteinyl protease substrates, according to the following FORMULA I, D or HJ namely, wherein Ri is an unnatural ammo acid side chain, preferably a lower alkenyl or lower alkynyl that is unsubstituted, or alternatively, substituted with W, W, in turn, is halo, hydroxy, alkyl, aryl, heterocycle, heteroaryl, alkoxy, aminosulfonyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocycle-carbonyl, nitro, haloalkyl, preferably, tnfiuoromethyl, cyano, amino or aminocarbonyl, and most preferably, a side chain not present in a natural ammo acid, X is -CH=CrHCH=CH) k -(CH 2 ) j or -CH 2 CH 2 -(CH 2 ) b where "k" is 0-9, preferably 0-3, and most preferably 0, "j" is 0-4, preferably 0-2, most preferably 0, and, "b" is 0-6, preferably 3-6, most preferably 3 or 4, Y is S, SO, S0 2 , NR 20 , -N(O)(R 20 )-, -PR20, -P(O)(R 20 )-, -P(0)0- or -P(0)(OR 2 o)0-, wherein, R 2 o is hydrogen, alkyl or aryl, Z is -(CH 2 ),-A, "i" is 0-4, preferably 0-2, most preferably 0, wherein, A is a substituted or unsubstituted heterocycle, heteroaryl or aryl, where the substituents consist of one or more L groups wherein, L is halogen, lower alkyl, lower alkenyl lower alkyn>l, alkoxv, arylox) , hydroxy, haloalkyl, preferably tnfiuoromethyl, nitro, nitrile, alkylthio, phen\l, and -NR 3 0R 31 , and, in optional embodiments L may be further substituted with W, as set forth above, but preferabl) L is selected from the substituents set forth in regard to V, below, R 30 and R 31 are each independently H, alkyl, preferably lower alkyl, hydroxy or halo lower alkyl, and most preferably tnfiuoromethyl, V is OH, halogen, lower alkyl, preferably methyl or ethyl or halogen-substituted lower alkyl, preferabl) halogen substituted methyl or ethyl, and is more preferably OH, R 2 , R 3 , R , R5, «, R7, R«, Q and n are each selected from (i), (11), (111), (IV), (v), (vi) and (vn) as follows, (i) R 3 and R 5 are each independently selected from a side chain of a naturally occurnng α-amino acid, H, alkyl, preferably lower ( -β) alkyl, alkenyl, preferably C 2 10 alkenyl, alkynyl, preferably C 2 ^ alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkeπyl, heteroaralkynyl, L-substituted aryl, L-substituted aralkyl, L-substituted aralkenyl, L-substituted aralkynyl, M-substituted heteroaryl, M-substituted heteroaralkyl, M-substituted heteroaralkenyl and M-substituted heteroaralkynyl, wherein, M is lower alkyl, preferably C \ ^ alkyl, or alternatively , M is halo-lower alkyl, preferably C haloalkyl, but most preferably M is tnfiuoromethyl, R 2 , R«, R«, and R« are each independently selected from among H, lower alkyl, preferably C alkyl, cycloalkyl, preferably lower cycloalkyl, and cycloalkylalkyl, preferably lower cycloalkylalkyl, R 7 is selected from among C^ alkyl, RA BCH, L-substituted or unsubstituted aryl, alkenyl, alkynyl, 9-fluorenyl, aralkyl, aralkenyl, aralkynyl, L-substituted or unsubstituted monocylic or bicychc heterocycle, L-substituted or unsubstituted monocychc or bicychc aryl, L-substituted or unsubstituted bicychc aryl-heteroaryl, and L-substituted or unsubstituted monocychc or bicychc heteroaryl, Q is -C(O)-, -O-C(O)-, -S(0) 2 - or -HN-C(O)-, R A is -(T) m -( ) m ,-R 3 , wherein T is O or NH, D is C|_< alkyl or C 2 - 4 alkenyl R B is selected in the same manner as in regard to R 3 and R 5 , above, or (ii) R 2 , R s and R are selected as in (1), above, R 3 and are selected as in either of (1), above, or (ι% ), below, n is zero, and R« and R 7 together with the atoms to w hich each is attached form a 3- 10 membered ring, preferably a 4-8 membered nng, most preferably a substituted or unsubstituted 5-6 membered heterocyclic moiety containing 1 -5 heteroatoms, where the substituents of the nng are selected either from those identified in regard to L, above, but, preferably those identified in regard to V, above, and most preferably the substituents so chosen will, together with the nng members will form a morphohno, thiomorpholino, pyrrohdinyl, V-substituted pyrrolidinyl, or 4-hydroxypyrrolidinyI nng, or (iii) R 2 , R 3 , R 4 , R 5 and Rg are selected as set forth in regard to (1), above, R« and R 7 are substituted or unsubstituted carbonyl (-(C = 0)-), phenyl, a heteroatom, lower alkylene, preferabIyC2 3 alkylene, or lower alkylene linked to a heteroatom, preferablyC 2 3 alkylene linked to a heteroatom, together with the atoms to which they are attached R and R 7 form a cyclic moiety, preferabl) a 4-6 membered cyclic or 8- 12 membered bicychc moiety, most preferably the sub j ect moiety is succinimidyl, phthalimidy! or maleimidyl, and, wherein the substituents are selected from those set forth in regard to L, above, but preferably those set forth in regard to V, above, and (iv) R 2 , R 5 , R«, R 7 , R $ , Q and n are selected as set forth above in regard to any of (ι)-(ιιι), above, or (v)-(vιi), below, R 3 and R< are substituted or unsubstituted lower alkylene, preferably C alkylene, or lower alkylene linked to a heteroatom, preferably C 2- 4 alkylene linked to a heteroatom, or a heteroatom, together with the atoms to which they are attached, R , and R 4 form a heterocyclic moiety, preferably a 4-6 membered heterocyclic moietv, most preferabl) morphohno, thiomorphohno, pyrrolidinyl, or V-substituted pyrrolidinyl, particularly 4-hydroxypyrrolιdιnyl, wherein, the substituents of R 3 and or R 4 are selected from those set forth in regard to L, above, but preferably to those set forth in regard to V, above, or (v) R 2 , R 7 , Rg, Q and n are selected as set forth in regard to (1), above, R 3 and R are selected as in either of (1) or (iv), above, R 5 and R« are each independently substituted or unsubstituted lower alkylene, preferably C 2 _, alkylene, or lower alkylene linked to a heteroatom, preferabl) C 2- 4 alkylene linked to a heteroatom, or a heteroatom, together with the atoms to which they are attached R 5 and R« form a heterocyclic moiety, preferably a 4-6 membered heterocyclic moiety, most preferably a moiety selected from among morphohno, thiomoφholino, pyrrolidinyl, or V-substituted pyrrolidinyl, particularl) 4-hydroxypyrroIιdιnyl, wherein, the substituents of R5 and or R$ are selected from those set forth in regard to L, above, but preferably to those set forth in regard to V, above, or (vi) R 2 , R« and R« are selected as set forth in regard to (1), above, R 3 and R« are selected as in cither of (1) or (iv), above, n is zero, and R 5 and R 7 are substituted or unsubstituted lower alkylene, preferably C 2 .- 1 alkylene, or lower alkylene linked to a heteroatom, preferably C - alkylene linked to a heteroatom, or a heteroatom, together with the atoms to which they are attached R 5 and R 7 form a heterocyclic moiety, preferably a 4-6 membered heterocyclic moiety, most preferably selected from among oφholino, thiomoφholino, pyrrolidinyl, or V-substituted pyrrolichnyl, particularly 4-hydroxypyrrolιdιnyl, wherein, the substituents of R 5 and/or R are selected from those set forth in regard to L, above, but preferably to those set forth regard to V, above; or (vii) R 2 , R 5 and R g are selected as set forth in regard to (ι>, above, R 3 and R < are selected as in either of (1) or (iv), above, R t and R 7 together with the atoms to which each is attached form a 6- 12 preferably an 8- 10 membered bicychc heterocyclic or heteroar)! moiet) , preferabl) a reduced isoquinolinyl moiety, more preferably a 1 ,2,3,4-tetrahydroιsoquιnolιnyl moiety, and in all of (ι)-(vn), above, unless specified otherwise (a) the carbon chains, where so indicated, are straight or branched chain containing from 1 to about 12 carbons preferabl) 1 to about 6, and most preferably 4 to about 6 carbons, and (b) the cyclic moieties, where so indicated, contain one ring or two fused rings, each ring or combination of rings, preferably containing 3 to about 16 atoms, most preferably 4 10 about 12 atoms, and in a combination of two fused nngs most preferably each of the subject rings contains 4 to about 6 nng atoms Abbreviations used are e g , AD, Alzheimer's disease, Aβ, Aβ-amyloid peptide, APP, amyloid precursor protein, APP7 51 , wild-type human APP-751 protein, APP 6 9 5 τ, wild-type human APP-695 protein, APP 6 7o/67i, human APP-695 protein harboπng the "Swedish" double mutation at codons 670 and 671 , APP 6 7o/ 6 7i/ i7, human APP-770 protein containing the "Swedish" double mutation at codons 670 and 671 and a Phe for Val substitution at codon 717 (codons numbered according to the APP-770 amino acid isoform), α-sAPP, soluble APP, mAb, monoclonal antibody, PBS, phosphate-buffered saline, FBS, fetal bovine serum, SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel el ctrophoresis, DMSO, dimethylsulfoxide The terms used herein are intended to have meaning as follows namely, "Alkyl" is intended to mean straight, branched-chain or cyclic hydrocarbon chain composed of a number of carbon atoms that is commonly specified according to a formula Where not specified, alkyl groups in the instant compositions preferably contain about 1 to about 12 carbon atoms ( .u) Representative examples of the subject alkyl groups include methyl, ethyl, propyl, cyclopropyl, isopropyl, n-butyl, t-butyl, sec-butyl, cyclobutyl, pentyl, cyclopentyl, n-hexyl, n-nonyl, n-decyl, cyclohexyl, cyclohexylmeth)!, cyclohexylethyl, and the like "Alkenyl is intended to mean a straight, branched-chain or cyclic hydrocarbon chain composed of one or more double-bonded carbon atoms, a number of which carbon atoms is commonly specified according to formula Where not specified, alkenyl carbon chains in the instant compositions preferably contain about 2 to about 12 carbon atoms (C 2 12 ), and preferably about 2 to about 7 carbon atoms (C 2 7 ) The subject C 2 12 alkenyl carbon chains contain about 1 lo about 6 double bonds, while C 2 7 alken)! carbon chains preferabl) contain about 1 to about 3 double bonds Representative alkenyl moieties include 2-methyl-2-propenyl, 2-methyl-l-propenyl, propenyl, l -butenyl, 2-butenyl, 3-butenyl, 2,2-dιfluoroethenyl, as well as, those straighi and branched chain moieties having up to two double bonds Cyclic alken)l carbon moieties preferabl) contain one or two fused hydrocarbon ring moeities having about 3 to about 16 carbon atoms (C 3 \β), and most preferably having about 4 to about 12 carbon atoms (C ι 2 ) "Alkynyl" is intended to mean a straight, branched-chain or cyclic hydrocarbon chain composed of one or more tπple-bonded carbon atoms, a number of which carbon atoms is commonly specified according to formula Where not specified, alkynyl carbon chains in the mstani compositions preferably contain about 2 to about 12 carbon atoms (C 2 - 12 ) with, preferably, about 1 to about 6 tnple bonds, and the alkynyl carbon chains of 2 to 6 carbons (C ^), preferably, contain 1 to 3 tnple bonds Representative alkynyl moieties include propynyl Cyclic carbon alkynyl moieties preferably contain one or two fused hydrocarbon nng moeities having about 3 lo about 16 carbon atoms (C 3 ie), and most preferably about 4 to about 12 carbon atoms (C 4 ι 2 ). "Lower alkyl", "lower alkenyl" and "lower alkynyl" are intended to mean alkyl, alkenyl and alkynyl hydrocarbon chains, respectively (as defined supra), each of which chains contains fewer than six carbon atoms "Cycloalkyl" is intended to mean an unsaturated carbon bond single nng system moiety, or an unsaturated carbon bond muluple cyclic ring system moiety Preferably, the subject cycloalkyl consists of about 3 to about 10 carbon atoms, and most preferably, the subject cycloalkyl consists of about 3 to about 6 carbon atoms Representative example of the subject ring system moieties include one, two or more rings that are joined together in a fused, bπdged or spiro-connected fashion, each of which moieties may be optionally substituted with one or more alkyl group substituents "Cycloalkenyl" is intended lo mean a single ring system moiety, or a multiple ring system each of which moieties has at least one carbon-carbon double bond, and each of which moieties preferably contains about 3 to about 10 carbon atoms (C 3 10 ), and most preferabl), about 4 to about 7 carbon atoms (C 7) Representative example of the subject ring system moieties include one, two or more πngs that are joined together in a fused, bridged or spiro-connected fashion, each of which moieties may be optionally substituted with one or more alkyl group substituents "Cycloalkynyl" is intended to mean a single nng system moiety, or a multiple ring system each of which moieties has at least one carbon-carbon tnple bond, and each of which moieties preferably contains about 3 to about 10 carbon atoms (C3. 1 0), and most preferably, about 8 to about 10 carbon atoms (Cg.io) Representative example of the subject ring system moieties include one, two or more πngs that are joined together in a fused, bπdged or spiro-connected fashion, each of which moieties may be optionally substituted with one or more alkyl group substituents. "Heteroatoms" is intended to mean that the subject atoms are not the same. Where not specified, heteroatoms in the instant compositions are commonly non- carbon atoms which are preferably are selected from among Oxygen (O), Nitrogen (N) and Sulfur (S) Substituents containing heteroatoms may be straight chain, branched chain or heterocyclic "Aryl" is intended to mean an aromatic hydrocarbon cyclic moiety, specified according to formula. Where not specified, in the instant compositions preferably the aryl moieties contain about 3 to about 14 carbon atoms (C 3 u) bonded into about 1 to about 2 nng structures "Lower aryl" is intended to mean that the subject aryl moiety, defined supra, preferably contain about 5 to about 7 carbon atoms in the subject nng structure "Aralkyl' is intended to mean that the subject aryl moiety, defined supra, is additionally substituted with one or more alkyl groups, as defined supra Representative examples of aralkyl and aryl moieties include phenyl, benzyl, phenethyl, 1 - and 2-naphthyImethyI, 1- and 2-naphthyl, 1 - and 2-ιndenyl, pentalenyl azulen) ! heptalenyl, acenaphthylen)l, 9-fluorenyl, phenalenyl, phenanthrenyl anthracenyl, tπphenylen)l, pyrenyl, chrysenyl, naphthacenyl, and the like "Heterocycle' , and ' heterocyclic' , are intended to mean a cyclic carbon atom ring moiet) composed of about 3 to about 14 atoms (C 3 )4 ), preferabl) about 3 atoms to about 7 atoms constituting about 1 to about 2 ring moieties, of which atoms, one or more atoms are heteroatoms, as defined supra, and the subject preferred heteroatoms are as set forth above Representative heterocycies include aliphatic saturated carbon nng moities bonded with unsaturated heteroaryl ring moieties Representative examples of heterocycies include pyrrolidinyl, pipeπdinyl, alkylpipeπdinyl 1 ,4-dιoxanyl 1 ,4-dιthιanyl, 1,4-moφholιnyl, 1 ,4-thιomoφholιnyI, 1 ,2,3-oxadιazolyl, 1 ,3,5-tπthιanyl or 1,2,5-tπazolyl "Heteroaryl' is intended to mean a cyclic carbon atom nng moiet) composed of about 3 to about 14 atoms (C 3 u), preferably about 3 atoms to about 7 atoms constituting about 1 to about 2 nng moieties, of which atoms, one or more atoms is a heteroatom, as defined supra. The subject preferred heteroatoms are as set forth above, and most preferably at least one nng moiety compπses an aromatic ring Representative examples of heteroaryls include furyl, thienyl, pyπdyl, pyrrolyl, N-methylpyrrolyl, pyranyl, indolyl, quino nyl, isoquinohnyl, cinnolinyl, quinoxalinyl, naphthyridiπyl, benzothiazolyl, dibenzothiazolyl, xanthenyl and 1 ,2,3,4-tetrahydroisoquιnolinyl. "NR A R B " is intended to mean a chemical moiety in which a nitrogen atom (N) is bonded to both an R A substituent and an R B substituent. In certain alternative embodiments, one or more R group substituents, e.g , R 3 , R 5 , and the like, of Formula L, II or HI, supra, may be identical with a side chain residue of a "naturally occurring amino acid". "Naturally occurring amino acids", and their constituent "side chain residues" are known in the art . "Natural side chain residues of naturally occurring amino acids", as used herein, is intended to mean natural substituents attached to the α-carbon atom of a naturally occurring amino acid synthesized by a plant or an animal. Representative examples of natural side chain residues include the hydrogen atom attached as a substituent at the α-carbon in glycine, the methyl group attached at the α-carbon in alanine, the isopropyl group attached at the α-carbon in vahne, and the like "Halogen", "halide" and/or "halo" are used interchangeably to refer substituents selected from among a fluorine atom (F), chlorine atom (CI), bromine atom (Br), iodine atom (I), as well as pseudohalide atoms Where not specified, halogen in the instant compositions preferabl) contain one or more atoms selected from among fluorine, chloπne, bromine and iodine "Pseudohalides" is intended to mean atoms, or chemical constituent groups, that have one or more chemical properties and/or chemical reactivities substantial!) similar to a halogen The subject constituent groups are distinguished by being interchangeable with halogens in the instant synthetic methods, as disclosed further belov, . Representative examples of pseudohalides include, but are not limited to. cyanide, cyanate, thiocyanate, selenocyanate, azide and trifluoromethyl. "Haloalkyl" is intended to mean an alkyl group substituted with one or more halogens. "Halo-lower alkyl" is intended to mean an alkyl moiety containing six or fewer carbon atoms which is substituted with one or more halogens. Where not explicitly specified otherwise, preferred halo-lower alkyl moieties in the instant compositions are selected from among -CF 3 , -CF 2 H, -CFH 2 , -CH 2 CI and -CH ∑ Br "Haloalkoxy' is intended to mean an RO- moiety in which R is a haloalkyl group "Aminocarbon)!' is intended to mean an -C(0)NH 2 moiet) "Alkylaminocarbonyl' is intended to mean an -C(0)NHR moiety in which R is hydrogen, alkyl, preferably lower alkyl or aryl, preferably lower aryl "Dialkylaminocarbonyl " is intended to mean an -C(0)NR'R moiety in which R' and R are independently alkyl or aryl, preferably lower alkyl or lower aryl, "Carboxamide' is intended to mean groups of formula -NR'COR "Alkoxycarbonyl" is intended to mean an -C(0)OR group in which R is alkyl, preferably lower alkyl or aryl, preferably lower aryl "Alkoxy is intended to mean an RO- group in which R is alkyl, preferabl) a lower alkvl or aryl, and most preferabl) a lower aryl "Thioalkox) is intended to mean and RSO- group in which R is alky I, preferabl) a lower alk) 1 or aryl, and most preferably a lower aryl "Alkylene is intended to mean a straight, branched or cyclic hydrocarbon moiet), preferabl) a straight or branched moiety composed of about 1 to about 20 carbon atoms (d 20 ). and most preferabl) composed of fewer than about 12 carbon atoms (Ci 12 ) In presently preferred embodiments, the alkylene moiety is either unsubstituted, or alternatively, is substituted with one or more alkyl groups, as defined supra In certain alternative embodiments of the invention, the subject hydrocarbon moiet) making up an alkylene additionally contains one or more heteroatoms selected from among oxygen and nitrogen In other embodiments, the latter subject nitrogen heteroatom can constitute an amide nitrogen bonded with an alkyl group Representative examples of alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-(CH 2 ) 3 -), cyclohexylene (-C«H,0-), methylenedioxy (-O-CH 2 -O-) and ethylenedioxy (-0-(CH 2 ) 2 -0-) "Lower alkylene" is intended to mean an alkylene moiety composed of fewer than about 6 carbon atoms In certain preferred embodiments, lower alkylene groups contain about 2 to about 3 carbon atoms "Alkenylene" is intended to mean a straight, branched or cyclic hydrocarbon, preferably straight or branched chain composed of about 2 to about 20 carbon atoms (C 2 . 2 o) at least two of which are double bonded one to another. In certain presently preferred embodiments of the invention, the subject alkenylene moiety is preferably composed of about 2 lo about 12 carbon atoms (C 2 .ι 2 ), and in most preferred embodiments the subject moiety preferably consists of a "lower alkenylene" having about 2 to about 6 carbon atoms. In certain alternative embodiments, the subject alkenylene moiety may be composed of a compound substituted at one or more positions in the straight, branched or cyclic hydrocarbon with one or more alkyl groups, as defined supra. In other alternative embodiments, the subject straight, branched or cyclic hydrocarbon may contain one or more heteroatoms, i.e., in place of one or more carbon atoms. In the latter case, the subject heteroatoms are preferably oxygen, sulfur or nitrogen atoms. The latter nitrogen atom may, in other alternative embodiments, constitute an amide nitrogen bonded with an alkyl group. Representative examples of alkenylene groups include - CH=CH - CH=CH -, -CH=CH- and -CH=CH-CH2-. "Lower alkenylene" is intended to mean an alkenylene having about 2 to about 6 carbon atoms, and preferably about 2 to about 4 carbon atoms. "Alkynylene" is intended to mean a straight, branched or cyclic hydrocarbon, preferably straight or branched chain composed of about 2 to about 20 carbon atoms (C 2 - 20 ) at least two of which are triple bonded one to another. In certain presently preferred embodiments, the subject alkynylene moiety preferably comprises about 2 to about 12 carbon atoms (C 2 .i 2 ), and in most preferred embodiments the subject moiety consists of a "lower alkynylene" having 2 to about 6 carbon atoms. In certain alternative embodiments, the subject alkynylene moiety may be composed of a compound substituted at one or more positions in the straight, branched or cyclic hydrocarbon with one or more alkyl groups. In other alternative embodiments, the subject straight, branched or cyclic hydrocarbon may contain one or more heteroatoms, i.e., in place of one or more carbon atoms. The latter heteroatoms are preferably oxygen, sulfur or nitrogen atoms. The latter nitrogen may, in other alternative embodiments, constitute an amide nitrogen bonded with an "alkyl group substituent", as defined below. Representative examples of alkynylene groups include -C≡C-C≡C-, -C≡C- and -C≡C-CH2-. "Lower alkynylene" is intended to mean an alkynylene composed of about 2 to about 6 carbons In presently preferably embodiments of the invention, lower alkyn) lene moieties are composed of about 2 to about 4 carbon atoms "Arylene" is intended to mean a monocychc or polycyclic hydrocarbon ring moiety having one or more aromatic/aryl groups as constituents in the subject nng moiety, and additionally, having one or more carbon-carbon double bonds The arylene moiety is preferably composed of 3 to about 20 carbon atoms (C 3 . 2 o). In presently most preferred embodiments, the subject arylene groups are composed of about 3 to about 12 carbon atoms (C 3 .ι 2 ), and most preferably, the arylene group is a "lower arylene" (C $ - ) In alternative embodiments, the subject arylene moiety may, in turn, be substituted with one or more aryl groups, and the arylene cyclic ring form a) also, optionally, contain one or more heteroatoms The latter heteroatoms constituting the arylene cyclic nng are preferably oxygen, sulfur or nitrogen, and the subject nitrogen atom may, in other embodiments, constitute an amide nitrogen bonded to an "alkyl group substituent". Representative examples of arylene groups include 1 ,2-, 1 ,3- and 1 ,4-phenylenedιamιne. "Lower arylene" is intended to mean an arylene group having about 8 to about 10 carbon atoms (C$ ιo) "Alkylidene" is intended to mean a =CR'R' substituent group, in this case, attached to a basal hydrocarbon core structure such as a =CR'R" group substituent of an alkylene or a heterocycleene In the latter case, the =CR'R" substituent group is attached to the core structure through the group's carbon-carbon double bond (=C-) Representative examples of alkylidene groups include methyhdene (=CH 2 ) and ethyhdene (=CHCH 3 ). "Arylalkylidene" is intended to mean an alkylidene group, i.e., =CR'R", in which either the R' or the R" substituent constitutes an aryl group "Carbonyl" is intended to mean a bivalent carbonyl group of the general formula (-(C=0)-). "Aikyl group substituent" is intended lo mean a hydrocarbon, a halo- hydrocarbon or a halogen-containing substituent to a core structure as follows namely, in presently preferred embodiments, the subject "alkyl group substituent" is halo-Iower-alkyl, aryl, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxy, alkoxycarbonyl, an oxygen atom or a cycloalkyl group "Aryl group substituent' , when used in regard to a core structure that is alkyl, cycloalkyl, cycloalkylalkyl, aryl, or a heteroaryl moiety, is intended to mean that the subject core structure is substituted with 1 or more, and preferably 1 to about 3, "aryl group substituents" selected from the following namely, halogen atoms, alkyls, halo-alkyls, arylalkyl, heteroarylalkyl, alkenylene, alkynylene and hydroxyl In presently preferred embodiments of the invention wherein the core structure is a halo-lower-alkyl, the preferred ' aryl group substituents' are tnfiuoromethyl, formyl, alkylcarbonyl or substituted ore unsubstituted arylcarbonyl In the latter case the substituents comprise 1 or more, and preferably 1 to about 3 groups selected from among the following namel), halogen atoms, halo-alkyls, alkyls, heteroarylcarboπyls, carbox) ls, alkoxycarbonyls, aryloxycarbonyls, aminocarbonyls, alk)lamιnocarbonyls, ,dιaIkylamιnocarbonyls, arylamino-carbonyls, diarylaminocarbonyls, arylalkylaminocarbonyls, alkoxys, aryloxys, perfluoroalkox)s, alkenyloxys, alkynyloxys, arylalkoxys, aminoalkyls, alkylaminoalkyls, dialkylaminoalkyls, arylaminoalkyls, amino groups, alkylamino groups, dialkylamino groups, arylaminos, alkylarylaminos, alkylcarbonyla inos, arylcarbony , amines, azidos, nitrogen atoms, thiol groups, alkylthiol groups, arylthiols, perfluoroalkylthiols, thiocyano groups, isothiocyano groups, alkylsulfinyl groups, alkylsulfonyls, arylsulfinyls, arylsulfonyis, aminosulfonyls, alkylaminosulfonyls, dialkylaminosulfonyls and arylaminosulfonyl groups "Aminosulfonyl' is intended to mean either an -NHSO 2 - substituent or an -SO 2 NH- bivalent group "Amido" is intended to mean either a -C(0)NH- or an -HNC(O)- bivalent group Thioamido" is intended to mean either a -C(S)NH- or an -HNC(S)- bivalent group "Oxyamido" is intended to mean a -OC(0)NH- or an -HNC(0)0- bivalent group "Thiaamido" is intended to mean a -SC(0)NH- or an -HNC(0)S- bivalent group "Dithiaamido" is intended to mean a -SC(S)NH- or an -HNC(S)S- bivalent group. "Ureido" is intended to mean an -HNCONH- bivalent group "Thioureido" is intended to mean an -HNCSNH- bivalent group "Alzheimer's disease" is the most common form of dementia affecting nearly 25% of the elderly population over the age of 85 years. Alzheimer's disease (AD) can now be diagnosed with a considerable degree of accuracy with 90% correspondence between clinical diagnosis and autopsy confirmation at certain centers The charactenstic histopathologic changes at autopsy include neurofibπllary tangles, neuπtic " senile" plaques, neuronal loss and amyloid angiopath) ( 1 ) The ma j or constituent of plaques (plaques) is a 4.2kDa fibπllogenic polypeptide of 42-43 ammo acids in length and referred to as amyloid beta-protein (abbreviated Aβ) Aβ is derived b) proteolytic cleavage from amyloid precursor protein (APP, 2-5) and accumulates in the cerebral extracellular perivascular matix in patients with AD, where its observance is considered to be a pathological landmark of the disease When aggregated in fibπllar beta-pleated sheet configurations, Aβ is thought to form a nidus for binding of other proteins that may contribute to pathology Binding of Aβ to neurons can result in increased vulnerability to excitotoxicity, generation of oxygen free radicals, impaired membrane transport systems, inhibition of glutamate receptors and induction of apoptosis (6) Neuronal loss can lead to disruption and defects in neurotransmission, cell-cell communications and abnormal production of extracellular matnx proteins In addition, deposition of Aβ in and around cerebral blood vessels, i.e., cerebral amyloid angiopathy, has been associated with hemorrhagic stroke in the elderly and patients with AD. "Amyloid precursor protein", abbreviated APP, is intended to mean an ammo acid sequence of Accession No. 1070623 (Entez- www ncbi.nlm.nih.gov), having 695 or 770 amino acids, and sequences related thereto e.g. by conservative amino acid substitution and the like. Representative proteins have one or more of the following attributes: namely, a calculated theoretical molecular weight about 86,943, encoded by a gene mapping to 21q21.2 and 2-21q21.2, alternatively spliced to encode either a protein of 695 aa or 770 aa as a C-terminal extended polypeptide with a Kunitz-type serine protease inhibitor domain, Gly7oo-Leu7 23 being the transmembrane domain, and Lys 723 -Phe$ 5 or Lys 723 -Asn 77 o being the cytoplasmic domain. "Aβ domain", also referred to as Aβ-peptide", and abbreviated "Aβ", is intended to mean a cleavage product of APP, supra, as mediated by one or more proteases at an APP NH 2 -terminal Lys 6 7o-Met67i or Mets7i-Asp 672 residue and a COOH-terminal or at a COOH-terminal Ala 7I3 -Thr 7 | 4 . being Asp 6 7 2 -De7i 2 ; "Aβι. 39 " being Asp 6 72-Val 7 n; Aβι._i2 being Asp 6 7 2 -Thr 7 | 4 ; and "Aβι. 43 " being sp 7 2 -Val7i5. "Carboxy terminal fragment", abbreviated interchangeably CTF and iβ-CTF, is intended to mean the portion of APP (Accession No. 1070623) corresponding to an APP fragment having a molecular size on SDS-PAGE of about 9kDa to about 12kDa and or a sequence from about Asp67 2 to about Asn77o. "CTF 100", meaning carboxy terminal fragment of 100 amino acids in length, is intended to mean an APP fragment having an apparent molecular size on SDS-PAGE of about 9kDa to about 12kDa and a sequence from about Asp 672 to about Asn77o. "Soluble APP", abbreviated sAPP, is intended to mean the portion of APP (Accession No. 1070623) corresponding to an N-terminal fragment produced by α- secretase having a molecular size on SDS-PAGE of about 100 kDa to about 1 15 kDa and lacking the transmembrane (supra) and cytoplasmic (supra) domains of APP. "Treatment" is intended to mean a method of delivering to a subject in need thereof a pharmaceutical preparation according to the compounds of the invention with the aim of effecting a change in APP:Aβ processing in the subject in need thereof. The instant methods include delivering the preparation to a patient i) before the dysfunction has been diagnosed, e.g., prophylactic protocols delivered with the aim of preventing development of the dysfunction, as well as, n) after the dysfunction has been diagnosed, e g , therapeutic protocols That the subject treatments have fulfilled the intended aim of effecting a change in APP processing to Aβ in the subject will be evident by one or more of the following namely, (i) a change in the amount of Aβ or sAPP in a sample of a biological tissue or biological fluid collected from a treated patient, (n) a change in the amount of one or more APP Aβ processing proteins in a biological tissue or biological fluid collected from a treated patient, or, (ui) a change (increase or decrease) or complete elimination of one or more clinical indicia of disease, e g , diagnostic symptoms, in a treated patient "Dysfunction" is intended to mean a pathologic condition of APP processing to Aβ in a tissue, i e , one or more changes in APP processing and/or production of Aβ as compared with the processing of APP occumng in a normal healthy control cohort For example the subject pathological conditions include, but are not limited to, 1) toxic amyloid dystrophy, (e g , chemical or drug-induced secondary amyloid dystrophy), n) vascular impairment with amyloid deposition, in) degeneration and peπpheral degeneration of vascular and/or neural tissue associated w ith amyloid deposition, iv) cellular detachment from basement membrane and defects in tissue organization visible microscopically in histology sections, e g , in the endothelium of vessels, v) amyloid containing lesions resulting following physical trauma, and v) hereditary am)loιd deposition in tissues, e g , systemic amyloidosis and familial Alzheimer s diseases "Subject in need thereof is intended to mean a mammal, e g , humans, domestic animals and livestock, having one or more dysfunctions of APP processing, as defined above "Biological fluid' as used herein is intended to mean a tissue fluid, such as cerebrospina! fluid (CSF), blood, plasma and serum, fluid collected from a body cavity (1 e , peπtoneal fluid, lung lavage fluid, urogenital mucus secretions, and the like), uπne, feces, sputum, sweat, and the like "Processing of APP to Aβ", abbreviated APP Aβ processing, is intended to mean intracellular pathways by which proteases act upon APP to catalyze hydrolysis of peptide bonds thereby liberating the Aβ fragment (as defined supra) of APP; in this case, including processes active in the following intracellular compartments: namely, in the endoplasmic reticulum; in the cytoplasm associated with ribosomes; in cytoplasmic vesicles (e.g., Golgi secretory vesicles); and, in lysosomal vesicles and the like. "Substantially pure" is intended to mean that the subject preparation is sufficiently homogeneous to appear free of detectable impurities as determined by standard methods of physicochemical analysis, e.g. IR, NMR, spectral methods for determining chirality and the like, or by separation methods, e.g., thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas liquid chromatography (GLC) such as subject to analysis by mass spectrometry (GCMS), or by another method employed to assess chemical purity. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification may increase the specific activity of the compound e.g. by isolating a single isostere. "Prodrug" is intended to mean one or more of the instant compounds in a form that, upon in vivo administration, is metabolized and/or otherwise converted from a form lacking in a biological or pharmaceutical activity, into a form having the subject activity. Representative examples of forms of prodrugs are disclosed e.g. in i Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press.New York, at pages 388-392. "Isostereoisomer", abbreviated isostere, is intended to mean of a compound possessing of one of two or more stereochemica! attributes expressed by one of the instant compounds, e.g. one spectral property. An isostere compound may exhibit a > biologic and/or a pharmacologic activity that is greater than, or less than mat of a racemic mixture of one of the instant compounds. "Alter APP processing to Aβ", is intended to mean altering the processing of APP. Two alternative processing pathways for APP may be represented as follows (the arrows represent cleavage sites): ingrediem in the composition or may be combined wu., other active ingredients. Liposome delivery systems are also contemplated, e.g , as disclosed in U.S. Patent No 4,522,81 1. The concentration of active compound(s) in the instant pharmaceutical composition will depend on absoφtion, mactivation and excretion rates of the active compound(s) (i.e., the selected compounds of FORMULA I, II and/or HI, above), the physicochemical characteristics of the compound(s), the dosage schedule, and amount administered as well as other factors known to skilled artisans. Typically a therapeutically effective dosage will produce a serum concentration of one or more of the instant compounds ranging from about 0.1 ng/ml to about 50-100 μg/ml serum or plasma. The pharmaceutical compositions typically should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram (kg) of body weight per day. Pharmaceutical dosage unit forms may be prepared to provide about I mg to about 1000 mg, preferably about 10 mg to about 500 mg of the instant compound The dosage and method of treatment will be determined by the physician after consideration of the general health, size and condition of a patient Effective concentrations (or amounts) of one or more of the compounds descnbed herein or pharmaceutically acceptable derivatives thereof may be mixed with one or more suitable pharmaceutical earners or vehicles Solutions or suspensions useful for parenteral, intrademnal, subcutaneous, or topical administration may include a sterile diluent such as water for injection, saline solution; a fixed oil, a polyethylene glycol, a glycerin; a propylene glycol or other synthetic solvent, one or more antimicrobial agents, e.g benzyl alcohol and methyl parabens; an antioxidant, e.g ascorbic acid or sodium bisulfite; a chelating agent, e.g ethylenediaminetetraacetic acid (EDTA), a buffer, e.g. an acetate, citrate or phosphate buffer; or, an isotonic agent e.g., sodium chloride or dextrose. Parenteral preparations may be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable materials. Methods for improving the solubility of the instant compounds, e.g., duπng administration and delivery from within the instant pharmaceutical compositions, include but are not limited to, uses of co-solvents, e.g., dimethylsulfoxide (DMSO), ■ c α-sAPP "Altering processing of APP to Aβ", abbreviated altering APP:Aβ processing, when used in regard to a composition containing one or more of the instant compounds is intended to mean that the subject composition is effective when administered to a cell, e.g., in tissue culture, to inhibit the production of carboxy terminal fragments of APP including iβ-CTF and or Aβ. While not wishing to be tied to any particular mechanism of action, representative examples of mechanisms by which the latter inhibitory effect on Aβ production may be exerted by the instant compounds include inhibiting: (a) an enzyme activity in a cell, e.g., an enzyme exhibiting a γ-secretase activity; (b) a co-factor binding to, and exerting an effect on, the subject enzyme activity in the cell, e.g , a cofactor increasing the catalytic efficienc) or turnover rate of an enzyme with a γ-secretase activity in a cell, (c) a transcription regulator, e.g., altering the level of expression of mRNA encoding the subject enzyme or cofactor protein in a cell, (d) a protein kinase, e.g., altering either the level of expression of, or the activity of, the subject enzyme in a cell, and (e) a phosphorylase, e.g., altering the activity of the subject enzyme in the cell The subject compositions may act directly on enzyme:cofactor:APP substrate complexes, or they may act indirectly, i.e., to change transcription or translation of enzyme proteins or cofactors. "Altering apoptosis" is intended to mean that the subject compound is effective to inhibit a cysteinyl protease activated in a cell which has been treated to induce programmed cell death Representative proteases so activated include calpains, caspases (e.g., caspases 3, 8 and 9), cathepsins and the like. Representative apoptosis inducer agents so able to induce apoptosis include Fas antibody, staurospoπne, interleukins EL-1 and TNF, glucose and oxygen deprivation during ischemic tissue injury and the like. Apoptosis may be induced in the cells of tissues subject to traumatic injury, restricted blood flow (e.g., during peripheral microvascular clotting and stroke) and the like. "Apoptosis" is intended to mean the cascade of energy (ATP) dependent events triggered by an apoptosis inducer agent and leading to programmed cell death through mechanisms commonly involving intracellular caspase enzymes, and commonly requiring about 12 to about 24 hours to accomplish the subject cell death. Apoptosis does not involve rapid, non-energy dependent lysis of cells, such as occurs during necrosis with release of cellular constituents (e.g., LDH) into the extracellular space. However, during apoptosis cells fragment their DNA and package it into membrane vesicles. Embodiments of the invention provide presently preferred compounds of FORMULA I, D and HI as set forth according to FORMULAS IV, V and VI: as follows, namely, wherein, all of the groups and substituents Jhereof, e.g. RpRg, Q, Y and Z are identical with those set forth in regard to FORMULA I, H and HI, above. In certain alternative preferred embodiments of compounds according to FORMULA IV, V or VI, when (Q)n is a carbonyl group and R| and R7 and the atoms to which they are attached form a heterocyclic ring moiety, the presently preferred ring moieties are succinimide, phthalimide or maleimide, and the most preferred is phthalimide. Similarly, when n is zero and R|, R7 and the atoms to which they are attached form a heterocyclic ring moiety, the preferred heterocyclic ring moieties are moφholino, thiomoφholino, pyrrolidinyl and V-substituted pyrrolidinyl, and most preferably 4-hydroxypyrrohdιnyI and 1,2,3,4-tetrahydroιsoquιnoIιnyI When π is zero and R 3 , Ri or R 2 , and R7 taken together with the atoms to which they are attached form heterocyclic moieties, then the preferred nng moieties are moφhohno, thiomoφholino, pyrrolidinyl, and V-substituted pyrrolidinyl, and most preferred is 4-hydroxypyrroIιdιn)l Representative examples of the presently preferred compounds include e g , N-Cbz-L-Leu-L-Leu-L-Leuene-phenyl vinyl sulfone, N-Cbz-L-Leu-L-Leu- D-Leuene-phenyl vinyl sulfone, N-(THJQ-carbonyI)-L-Leu-L- Leu-D-Leuene phenyl vinyl sulfone; N-(THIQ-carbonyI)-L-Leu-L-Leu-L-Leuene phenyl vinyl sulfone, N-(THIQ-carbonyI)-L-VaI-L-Met-L-Leuene phenyl vinyl sulfone, N-(THIQ-carbonyI)-L-VaI-L-Met-D-Leuene phenyl vinyl sulfone, N-0"HIQ-carbonyl)-L-Val-L-Leu-L-Leuene phenyl vinyl sulfone, N-(THIQ- carbonyl)-L-Val-L-Leu-D-Leuene phenyl vinyl sulfone, N-(4-benzylpιpeπdιnyl- carbonyl)-L-Leu-L-Leu-L-Leuene phenyl vinyl sulfone, N-(4-benzylpιpeπdιnyl- carbonyl)-L-Leu-L-Leu-D-Leuene phenyl vinyl sulfone, N-(4-benzylpιperazιnyI- carbonyI)-L-Leu-L-Leu-L-Leuene phenyl vιn)l sulfone, and, N-(4-benzylpιperazιnyl- carbonyl)-L-Leu-L-Leu-D-Leuene phenyl vinyl sulfone Embodiments of the invention prov ide pharmaceutical compositions in which the instant compounds are present as the salts of organic acids and bases (such as acetates, lactates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and the like), salts of inorganic acids and bases, e g , alkali metal salts of lithium, potassium, sodium, alkaline earth metals, such as barium, calcium and magnessium and the like, salts of transition metals such as Zinc, salts of mineral acids such as hydrochloπdes and sulfates, esters, acids, bases, solvates, hydrates, amine salts, phosphonates such as sodium hydrogen phosphate and disodium phosphate, and the like, including hydrolyzable prodrugs cleavable and activated in vivo to drugs, e.g , deπvatives of N,N'-dιbenzylethylenedιamιne, chloroprocaine, chohne, ammonia, diethanolamme and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, l-para-chlorobenzyI-2- pynolidin- l'-yl-rnethylbenzimidazole, diethylamine and other alkylamines, piperazme and tris(hydroxymethyI)amιnomethane and the like In other embodiments the invention provides a pharmaceutical preparation consisting of one or more isolated and substantially pure diastereoisomers or chiral forms of a pharmaceutical preparations according to FORMULA (I), (H) and/or (HI) Embodiments of the invention provide compounds according to FORMULA I, H or HI that are effective to modulate the activity of cysteinyl proteases including extracellular (secreted) proteases and inlracellular protease involved in protein processing. The instant protease inhibitors include inhibitors acting, e.g., by processes including both competitive and non-competitive inhibition. In yet other embodiments, the invention provides methods for administering to a subject in need thereof a concentration of one or more pharmaceutical preparations consisting of one or more compound according to FORMULA I, H and/or HI that is effective to ameliorate one or more symptoms of disease. Examples of subjects so-in-need include e.g. patients with systemic amyloidosis, Alzheimer's disease, atherosclerosis, restenosis following angioplasty, rheumatoid arthritis and connective tissue diseases, dermatologic diseases such as Epidermolysis bullosis, Systemic lupus erythematosus, Sjogren's syndrome, Insulin-dependent diabetes types I and H, atherosclerosis, stroke, traumatic neural degeneration, chronic vascular and respiratory disorders, necrotic and apoptotic tissue damage resulting from bacterial, fungal and viral infection, (e.g., AIDS dementia, adenovirus, HSV, HPV, influenza and the like), inflammatory bowel disease, irritable bowel syndrome, diarrhea, constipation, gastπc acid secretion and ulcers, complications resulting from co- medication or surgical procedures; or heart insufficiency, hypeφrolactinemia, asthma and arthπtis Embodiments also provide compounds according to FORMULA I, H or ID. that are capable of inhibiting the activity of a cysteinyl protease, e.g., an intracellular secretase such as β-secretase involved in processing of APP and production of Aβ, an intracellular apopain/caspase protease involved in programmed cell death (apoptosis), an intracellular protease involved in antigen processing, e.g. a cathepsin, or an extracellular protease involved in tissue destructive processes, e.g., in trauma or arthritis. That a compound is so active may be determined by conducting e.g. either an in vitro or an in vivo assay. For example, in an in vitro assay the instant compounds decrease in the activity of a cellular cysteinyl protease enzyme activity, or a secreted extracellular cysteinyl protease. Assays for cysteinyl proteases, as with assays for other proteases, are within the ordinary skill in the art In one representative example, the subject cysteinyl protease is an intracellular β-secretase enzyme involved in processing of APP and production of Aβ amyloidogenic polypeptides In the latter case a positive assay is recorded when one or more of the following are observed namely, (1) a decrease is observed in the 4-kDa amyloid Aβ in the medium relative to control cultures, and/or (2) the relative amount of sAPP, in the medium is observed to increase, (3) a decrease is observed in the amount of C-terminal APP fragments >9 kDa in cell lysates, i e , resulting from differential processing, and or (4) there is an observed increase in the amount of α-sAPP in the medium relative to control cultures In vivo, the instant compounds are preferably effective when administered to an experimental animal of AD or systemic amyloidosis to either ( I ) increase the levels of sAPP (e g , in brain, plasma or CSF), and/or (2) decrease the level Aβ in a biological fluid or tissue extract In one representame example, a positive assay result may be indicated as an increase in the ratio of α-sAPP to sAPP in a tissue sample from a pre-treatment to a post-treatment interval Representative methods for preparing the instant vinyl sulfones are depicted in the EXAMPLES, section below, and in particular in Reaction Schemes A-F of EXAMPLES 1 -14 In Scheme A, preparation of amino ester hydrochloπdes is depicted, Scheme B illustrates preparation of vinyl sulfones from the amino ester hydrochloπdes, in Scheme C, formation of di-and tπ-peptide vinyl sulfone analogs is depicted, Scheme D illustrates the preparation of an illustrative isomer of an amino vinyl sulfone, and, synthesis of illustrative N-protected tπpeptide vinyl sulfone analogs as 1,2,3,4-tetrahydro-ιsoquιnohnyl ureas is shown in Scheme E An alternative to the synthesis of Scheme E is presented in Scheme F, i e., 4- benzylpipeπdine or 1 -benzylpiperazine are substituted for 1 ,2,3,4,5-tetra- hydroisoquinohne As an alternative, an automated peptide synthesizer and solid phase sequential coupling procedures may be used to produce intermediates useful in final synthesis of the instant di- and tri-peptide inhibitors. For example, the instant compounds may be synthesized from their carboxyl terminal end toward their amino terminal end using sequentially protected amino acids, ammo acid derivatives and/or isomers, or spacer groups, according to the structure set forth in FORMULAS I, H and/or ED. A variety of solid phase resin supports are useful in this method including certain of those useful in the art for solid phase synthesis of peptides. One presently preferred resin comprises polystyrene cross-linked with from about 0.5% to about 3% modified divinyl benzene, wherein the modification involves benzhydrylamidalion, chloromethylation or hydroxymethylation. Modification is effective to produce sites that are useful for linking the instant di- and tri-peptide intermediates, e.g., through amide or ester bonds. One representative example of a hydroxymethyl resin is disclosed by Bodansky et al. W 966) Chem. Ind. (London) 38.1597-98). Preparation of illustrative chloromethyl- and benzhydrylamine-resins is disclosed in Stewart et al. ("Solid Phase Peptide Synthesis" 2nd Edition, Pierce Chemical Co., Rockford, Dlinois ( 1984), Chapter 2, pp 54-55). Dlustrative methods for coupling protected amino acids to a resin are disclosed by Gisin (( 1973) Helv Chem. Acta 56.1476). A variety of α-amino protecting groups may be useful in synthesis of the instant compounds and their intermediates Representative examples of such protecting groups as presently contemplated include: (i) acyl protecting groups such as formyl, trifluoroacetyl, benzoyl, phthalyl, p-toluenesulfonyl (tosyl), benzenesulfonyl, nitrophenylsulfonyl, tritylsulfonyl, o-nilrophenoxyacetyl, α-chlorobutyrl, 4-((4-chloro-phenyl)sulfonylamιnocarbonyl)phenylcarbonyI, and 4-((4-bromophenyl) sulfonylamino carbonyl) phenylcarbonyl; (ii) aromatic urethane protecting groups such as phenyloxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyls such as p-chlorobenzy[oxycarbonyl, p-methoxybenzy- [oxycarbonyl, p-nitrobeπzyloxycarbonyl, p-bromobenzyloxycarbonyl, I-(p-biphenyl)- 1-methyl-ethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzylo-xycarbonyl, and benzhydryloxycarboπyl, (iii) aliphatic urethane protecting groups such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxy-carbonyl, methoxycarbonyl, ethoxycarbonyl, isobutyloxycarbonyl and allyloxycarbonyl; (iv) cycloalkyl urethane protecting groups such as cyclopentyloxycarbonyl, adamantyloxycarbonyl, and cyclohexyloxycarbonyl, (v) thiourethaπe protecting groups such as phenylthiocarbonyl, (vi) alkyl type protecting groups such as triphenylmethy! (trityl) and benzyl (Bn), and (vii) alkyl and aryl silyl protecting groups such as tπmethylsilyl, tert-butyidimethylsilyl, tert-butyl-diphenylsilyl and tπisopropylsily t-butyloxycarbonyl (Boc) is one presently preferred α-amino protecting group Representative methods using Boc for protecting are disclosed by Bodansky et al in "The Practice of Peptide Synthesis, "Springer- Verlag, Berlin (1984), p. 20) The selection and use of an appropπate coupling reagent is within the skill in the art Particularly suitable coupling reagents where the amino acid to be added is Gin, Asn, or Arg include Λ/,/V-dιcycIohexyl-carbodnmide and 1-hydroxybenzotπazole The use of the latter reagents duπng synthesis of the instant compounds of FORMULA I, H and/or ETJ prevents nitrile and lactam formation Other suitable coupling agents include e.g , (l) carbodiimides such as l-(3- dιmethylamιno-propyl)-3-tehyl-carbodπmιde hydrochloride), (n) ketemmines, (in) isoxazolium salts such as N-ethyl-5-pheny -ιsoxazolιum-3-sulfonate, (iv) monocychc nitrogen-containing heterocyclic amides of aromatic character containing 1-4 ring nitrogen atoms, e g , lmidazo des, pyrazohdes and 1,2,4-tπ azohdes, and particularly N,N-carbonyldnmidazole and N,N-carbonyI-dι- l,2,4-tπazole, (v) alkoxylated acetylene e g., ethoxyacetylene, (vi) reagents which form a mixed anhydride with the carboxyl moiety of the ammo acid, e.g , ethyl chloroformate and isobutyl chloroformate, or alternatively, the symmetrical anhydπde of an amino acid to be coupled e , Boc-Ala-O-Ala-Boc, and (vn) nitrogen-containing heterocyclic compounds having a hydroxyl group on one nng nitrogen, e.g., N-hydroxyphthalimide, N-hydroxysuccιnιrτude and 1-hydroxybenzotπazole. Activating reagents, and methods of their use in peptide coupling, are known in the art, e.g. as disclosed in Kapoor ((1970) J Pharm Sci. 59.1-27). For synthesis of the instant compounds according to FORMULAS I, H and/or HI, presently preferred coupling agents are symmetncal anhydrides. For removal of a compound from a preferred beπzhydrylamine resin, treatment with a solution of dimethyl sulfide, p-cresol, thiocresol, or anisole in anhydrous hydrogen fluoride is presently preferred The cleavage reaction is also preferably carried out at a temperature between about 0°C and about room temperature, over a period of about 5 minutes to about 5 hours. Embodiments of the invention provide pharmaceutical compositions comprising one or more compounds according to FORMULA I, H and/or HI, above. Preferably, each of the instant compounds present in the pharmaceutical composition is present in a therapeutically effective amount. The instant pharmaceutical compositions find a variety of uses in treatments for neurological disorders, e.g., schizophrenia, Alzheimer's disease, disorders of extrapyramidal motor function, such as Parkinson's disease, progressive supramuscular palsy, Huntington's disease, Gilles de la Tourette syndrome and tardive dyskinesia, obesity, severe pain, drug and tobacco withdrawal, respiration, mood and emotional disorders- such as depression, anxiety and psychosis, motor control and function, focus and attention disorders, concentration disorders, memory loss, cognitive impairment, dementia (including AIDS dementia), neurodegenerative disorders, epilepsy; as well as in treatments of other diseases, e.g., cardiovascular dysfunction including hypertension and cardiac arrhythmias, convulsive disorders, eating disorders, including bulimia and anorexia, autonomic disorders including dysfunction of gastrointestinal motility and function such as inflammatory bowel disease, irritable bowel syndrome, diarrhea, constipation, gastric acid secretion and ulcers. The instant pharmaceutical compositions may also be useful as co-medication in surgical procedures and pheochromocytoma; or in co- treatments of heart insufficiency, hypeφroiactinernia, bacterial infections, asthma or arthritis. The instant pharmaceutical compositions are preferably formulated as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs. As such the compositions are useful for oral administration, or in sterile solutions or suspensions, for parenteral administration. Transdermal delivery, e.g., patch preparations, and dry powder inhalers are also contemplated. Examples of methods that may be useful for formulating the instant pharmaceutical compositions are disclosed e.g., by Ansel, Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, p. 126. The instant pharmaceutical compositions may be formulated as the sole pharmaceutically active surfactants, e.g., TWEEN, dissolution in aqueous sodium bicarbonate, and preparation of soluble derivatives or prodrugs of the instant compounds prior to formulation. Unit dosage forms suitable for administration to subjects in need thereof, e.g., as packaged individually, are known in the art. Each unit-dose commonly contains a predetermined quantity of the therapeutically active compound sufficient to produce a desired therapeutic effect; in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. Representative methods for preparing dosage forms are known in the art, e.g., see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. Oral pharmaceutical dosage forms including solid, gel and liquid are contemplated formed as tablets, capsules, granules, bulk powders, chewable lozenges enteric-coated capsules, sugar-coated or film-coated capsules, hard or soft gelatin capsules, granules e.g., as non-effervescent or effervescent forms, pills, troches and the like. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Parenteral injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0. 1 % w/w up to about 90% w/w or more, preferably more man 1 % w/w of the active compound to the treated tissue(s). Topical solutions, suspension, emulsions and the like may be formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, irrigations, sprays, nasal sprays, suppositories, bandages, dermal patches, transdermal delivery systems and the like. Contemplated formulations include inhalent aerosols in the form of an aerosol or nebulizer solutions, inhalent therapy solutions, microfine powders for insufflation, and the like. Also contemplated are formulations for skin and mucous membranes, ophthalmic uses (e.g., eyes), intra-cisternal and intra-spinal application. The pharmaceutical compositions containing compounds or pharmaceutically acceptable derivatives may be packaged as articles of manufacture containing e.g., a packaging material; the instant pharmaceutical composition; a product insert describing that the composition is effective in ameliorating one or more symptoms of disease, i.e., as set forth above; and, a label indicating that the composition containing the compound or derivative thereof is useful in the treatment or prevention of the disease, i.e., as set forth above. Embodiments of the invention provide compounds according to FORMULA I, H and/or HI that find uses in pharmaceutical compositions manufactured for the puφose of administering a treatment effective in altering apoptosis and altering processing of APP to Aβ, e.g., altering deposition of amyloid. The dose ranges, which can be established empirically, for use in the treatment of disease states will depend upon the etiology, nature, and severity of the disease state as well as such other factors as determined by the attending physician. The broad range for effective treatment is about 0.01 to 10 mg per kilogram (kg) of body weight per day. The preferred range is about 0. 1 to 10 mg/kg of body weight per day. Preferred modes of administration include oral and parenteral modes of administration. It is believed that the instant treatments for patients with such amyloid disorders will effect beneficial changes in the disease process resulting in a stabilization of disease activity, slowed progression of disease, and/or an enhanced lifestyle with increased cognitive ability and decreased anxiety, as well as a possible delay (or obviation) of the need to institutionalize certain patients. In other embodiments, pharmaceutical compositions are provided comprising the instant compounds of FORMULA L H and/or HI as formulated for use to alter apoptosis, e.g., by inhibiting the action of cysteinyl caspase proteases and/or cathepsin proteases. Ca + dependent proteases are presently thought to play significant roles in the pathology of a variety of disorders, including cerebral ischaemia, cataract, myocardial ischaemia, muscular dystrophy and platelet aggregation. The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. EXAMPLE 1 Solution Phase Synthesis: (2i?S)-2- rf-Butoxycarbonylamino-4-methyI-4-peπtenoic Acid A. Ethyl (2ΛS)-2-DipheπyImethyIenamino-4-methyl-4-pentenoate Sche e A I i) 1 0 M LiH M D S THF, -78° C . Ar II) R»-Br ] 1.B CI Ph NH.+ O = N IN aq HCI Ph El elhe r OEI R' R» R» C To a stirred solution of N-(diphenylmethylene)glycine ethyl ester (available from Aldrich Chemical Co., Milwaukee, WI) (50.0 g, 187 mmol) in dr)' THF (200 mL) at -78°C under argon was added a 1.0 M solution of lithium bis(trimethylsilyl)amιde (Li HMDS; 210 mL, 0.2 mol) in THF over a period of 45 min ("l.A, Scheme A). After 0.5 hour al -78°C, 3-bromo-2-methylpropene (18.91 mL, 187 mmol) was added dropwise to the orange-yellow suspension. After the addition was complete, the reaction mixture was stirred for an additional 0.5 hour at 0°C and then allowed to warm to room temperature. After 1 hour the reaction mixture was concentrated under reduced pressure to give an orange-colored oil. The crude material was dissolved in ethyl acetate (EA) (600 mL), washed with brine (100 mL), dried over anhydrous MgS0 4 and concentrated under reduced pressure to give the desired compound (60 g, 99%), which was used for the next step without further purification. Η NMR (CDC1 3 . 300 MHz), δ 7.1 - 7.7 (m, 10 H), 4.72 (dd, 2 H), 4.2 ( , 3H), 2.63 (m, 2H), 1.5 (s, 3H), 1.27 (t, 3 H). B. Ethyl (2ΛS)-2-Amino-4-methyl-4-pentenoate hydrochloride To a stirred solution of the alkylated Schiff s base from EXAMPLE 1.A above (60g, 0. 187 mol) in diethyl ether (1.2 L) was added 1 N aqueous HCI (500mL). The resulting biphasic mixture was stirred for 24 hours at RT. The aqueous layer was separated from the ether layer, washed twice with EA (200 mL) and the aqueous solution was concentrated under reduced pressure to give the desired product "B", Scheme A (36 g, 99%) as viscous oil. Η NMR (CDCb. 300 MHz) δ 5.1 (br s, I H), 4.9 (br s, 1 H), 4.32 (m, 3H), 2.5 -2.9 ( , 2H), 1.83 (d, 3H), 1.36 (t, 3H). C. Ethyl (2RS)-2-tert-Butoxycarbonylamino-4-methyl-4-pentenoate To a stirred solution of ethyl (2ΛS)-2-amino-4-methyl-4-pentenoate "B", EXAMPLE l.B, above, (6.0 g, 0.031 mol) in CH 2 C1 2 (75 mL) was added di-tert-butyl dicarbonate (Boc) 2 0; 6.79 g, 0.031 mol) followed by triethylamine fTEA, 8.7 mL, 0.062 mol) and the reaction mixture was left stirred at RT overnight. After overnight, the reaction mixture was diluted with water ( 100 L), the organic layer was separated and washed with 0.5 N aqueous HCI (75 mL), water (75 mL, dried over anhydrous Na 2 SO, and concentrated under reduced pressure to give a yellow oil. The resultant crude material was purified via chromatography on silica (hexanes (H):EA, 3: 1 ) to give ethyl (2R5)-2-tert-butoxycarbonylamino-4-methyl-4-pentenoate as a colorless oil (6.9 g, 87%). Η NMR (CDCI 3, 300 MHz) δ 4.9 (m, 1 H), 4.8 (br s, 1 H), 4.7 (br s, 1 H), 4.4 (m, 1 H), 4.2 (dq, 2 H), 2.3-2.6 (m, 2 H), 1.7 (s, 3 H), 1.42 (s, 9 H), 1. 25 (t, 3 H). D. (2J?S)-2-tert-ButoxycarbonyIamino-4-methyl-4-pentenoie Acid To a stirred solution of ethyl (2R )-2-ten-butoxycarbonylamino- 4-methy -pentenoate EXAMPLE l .C, above (6.9 g, 26.9 mmol) in acetone (50 mL was added LiOH (108 mL of 1 N aqueous solution, 108 mmol). The clear solution was stirred at room temperature for 0.5 hour. Acetone was evaporated under reduced pressure, the pH of the resulting aqueous solution was then adjusted to 3 by addition of 1 N HCI and the aqueous layer was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na 2 SO.j and concentrated under reduced pressure to give the desired acid as a pale yellow oil in quantitative yield. Η NMR (CDC1 3 . 300 MHz) δ 4.95 (m, 1 H), 4.9 (br s, 1 H), 4.8 (br s, 1 H), 4.4 (m, 1 H), 2.3-2.7 (m, 2 H), 1.76 (s, 3 H), 1. 5 5 (s, 9 H). EXAMPLE 2 (3ΛS)-l-PhenylsulfoπyI-3-amino-5-methyl-lE,5-hexadiene Hydrochloride A. N,0-Dimethyl (2.?5)-2-tert-ButoxycarbonyIamiπo-4-methyI-4- pentenoylhydroxamate To a solution of (2Λ5)-2-tert-butoxycarbonylamino-4-methyI-4-pentenoic acid (EXAMPLE 1 C; Scheme B) in CH 2 CI 2 (50 mL was added l-(3-dimethyI- aminopropyI)-3-ethyl-carbodiimide hydrochloride (EDC) (5.67 g, 0.296 mol) and NO-dimethylhydroxyiamine hydrochloride (MeHNOMe.HCI; 2.89 g, 0.0296 mol). The resulting suspension was cooled to 0 C C, TEA (4.12 mL, 0.0296 mol) was added dropwise and the reaction mixture was allowed to warm to room temperature and left stirring overnight. After overnight, the reaction mixture was poured into cold water (75 mL) and extracted three times with CH 2 CI 2 (350 mL). The organic layers were combined, washed with 1 N HCI (75 mL), brine (75 mL), dried over Na 2 S0 4 and concentrated under reduced pressure. The resultant crude product was purified by flash chromatography on silica gel using chloroform/methanol (99: 1) as eluant to afford the desired compound (7.33 g, 53%). Η NMR (CDCI 3 , 300 MHz) 5.2 (m, IH), 4.83 (br s, IH), 4.76 (br s, IH), 3.8 (s, 3H), 3.2 (s, 3H), 2.1-2.5 (m, 2H), 1.77 (s, 3H), δ 1.4 (s, 9H). B. (2ΛS)-2-ter(-Butoxycarbonylamino-4-methyl-4-pentenaI Lithium aluminum hydride (LAH, 0.42 g, 1 1 mmol) was suspended in anhydrous diethyl ether (50 mL). A solution of the Weinreb amide in diethyl ether ( 10 mL was added dropwise at 0°C. After 0.5 hour at this temperature, the reaction mixture was quenched by sequential addition of water (0,42 mL), 15% aqueous NaOH solution (0.42 mL) and water (1.26 mL). The precipitated inorganic salts were filtered through celite, and the filter pad washed with ether (50 mL). The filtrate was concentrated under reduced pressure to give the aldehyde as a clear viscous oil (3.35 g). The compound was used the same day for the subsequent steps without further purification. C. Diethyl (Phenylsulfonyl)methylphosphonate A stirred solution of methyl phenyl sulfone (20 g, 0.128 mol) in dry THF (200 mL) was cooled at -78°C in an acetone/dry ice bath. Lithium bis(trimethylsilyl)amide (Li HMDS; 134 mL, 1 M solution in THF, 0.134 mol) was added dropwise over 1 h. The resulting white suspension was stirred for an additional hour al -78°C and diethyl chlorophosphate (18.5 mL, 128 mmol) in THF (20 mL) was added. The reaction mixture was stirred al -78°C for 0.5 h, then allowed to slowly warm to room temperature and left stirring for 4h. The reaction mixture was next concentrated under reduced pressure, the residue was dissolved in EA (500 mL), washed with brine (100 mL),dried over anhydrous Na 2 Cθ3 and concentrated under reduced pressure. The resultant crude material was puπfied by flash chromatography on silica gel (EA H, 3.1 to 1 : 1) to afford the desired product as white solid (17.9 g, 48%). Η NMR (CDCI 3 , 300 MHz) δ 7.5-8 1 (m, 5 H), 4 16 (q, 4 H), 3 8 (s, I H), 3.74 (s, 1 H), 1.29 (t, 6 H) D. (3 ?S)-3-tert-Butoxycarbonylamino-5-methyI-l-phenyIsulfonyI- lE,5-hexadiene To a stirred solution of diethyl (phenylsulfonyl)methylphosphonate (from EXAMPLE 2.C) (3.54 g, 00121 mol) in dry THF (70 ml) at -78°C was added slowly a solution of lithium bιs(trimethylsilyl)amιde (LiHMDS, 13.2 ml, 1 M solution in THF, 13.2 mol) over 0 5 h The reaction mixture was stirred for another 0.5 h at -78°C, and a solution of crude (2Λ )-2-tert-butoxycarbonylamιno-4- methyI-4-pentenal from EXAMPLE 2 B (2 35 g, 1 1 0 mol) in dry THF (20 ml) was added dropwise Afler addition was complete, the reaction mixture was stirred for an additional 0 5 hour and then allowed to warm to room temperature and stirred for an additional 3 h The stiπed reaction mixture was concentraied under reduced pressure and the residue was dissolved in EA (100 mL) The EA solution was washed with bπne (50 mL), dried over MgS0 4 and concentrated under reduced pressure to give an oil The resultant crude material was purified via flash chromatography on silica gel (H.EA, 6.1) to provide the desired sulfone "D", Scheme B (1.82 g, 47% overall yield for 2 C and 2 D) Η NMR (CDCI 3 , 300 MHz) δ 7.9-7.5 (m, 5 H), 6.9 (br d, 1 H), 6 44 (d, 1 H), 4 88 (br s, 1 H), 4 76 (br s, 1 H), 4 5 (m, 2 H), 2 2-2 3 (m, 2 H), 1.72 (s, 3 H), 1.37 (s, 9 H) E (3RS)-l -PhenyIsulfonyl-3-amino-5-methyl-IE,5-hexadiene Hydrochloride To a stirred solution of the vinyl sulfone from EXAMPLE 2.D, nbove, (0.75 g, 2.13mmol) in CH 2 C1 2 (10 ml) was added HCI (10.5 mL of a 4 M dioxane solution, 43.0 mol). The reaction mixture was stirred at room temperature for 0.5 h and then concentrated under reduced pressure to provide 0.61 g (99%) of the desired product as a white solid. Η NMR (CD 3 OD, 300 MHz) δ 7.92-7.89 (m, 2 H), 7.72 - 7.61 (m, 3 H), 7.05- 6.83 (m, 2 H), 5.02 (br s, IH), 4.85 (br s, 1 H), 4.21 (q, 1 H), 2.6-2.48 (m, 2 H), 1.71 (s, 3 H). EXAMPLE 3 (3/?S)-L-L^u-N-[3-(l-phenylsulfonyI)-5-methylhexa-lE-5-dieneamide A. (J/?5)-N-Boc-L-Lcu-N-[3-(l -pheπylsulfonyl)-5-methylhexa- lE,5-dieneamide To a stirred solution of N-Boc-Leu-OH (available from Aldrich Chemical Co., Milwaukee, WI) (1.66 g, 6.7 mmol) in anhydrous CH 2 C1 2 (30 mL) at RT were added 1 -hydroxybenzotriazole (HOBt) (1.64 g, 12.1 mmol), EDC (1.28 g, 6.7 mmol), (5/?5)-l-phenylsulfonyI-3-amino-5-methyI-lE,5-hexadiene hydrochloride from EXAMPLE 2.E (1.74 g, 6.06 mmol) and di-isopropylethylamine (DEEA) (0.86 g, 6.7 mmol). The reaction mixture was stirred at room temperature for 17 h and then concentrated under reduced pressure. The residue was resuspended in ethyl acetate (EA) (100 mL, washed successively with saturated bicarbonate solution (50 mL), 10% citric acid (50 mL), and brine (50 mL), dried over anhydrous MgS0 4 , and concentrated under reduced pressure. The resultant crude product, ("F, Scheme C), was purified by chromatography (EA:H, 1 :2) to yield the desired product as colorless oil (2.19 g, 78%). Η NMR (CDClj, 300 MHz) δ 7.87-7.80 (m, 2 H), 7.61 -7.48 (m, 3 H). 6.9 (dt, 1 H), 6.5 (m, 1 H), 6.3 (m, 1 H), 6.15 (m, I H), 4.86 (br s, I H), 4.17 (br s, 1 H), 3.9 (m, 1 H), 2.2-2.4 (m, 2 H), 1.7 (s, 3H), 1.4 (br s , 9H), 0. 9 (m, 9 H). B . (3RS)-L-Leu-N-[ 3-(l-phenylsulfonyl)- 5- methy!hexa-lE,5- dieneamide This compound was prepared following the procedure of EXAMPLE 2.D and 2.E, above using (5R5-3-tert-butyoxycarbonylamino-5-isobutyl-l-phenylsulfoπyI- 1E,5 hexadiene as a starting material. Η NMR (CD 3 OD) δ 8.62-8.45 (m, 1 H), 7.77-7.70 (m, 2 H), 7.58-7.43 (m, 3 H). 6.80-6 71 (m, 1 H), 6.47-6.42 ( , 1 H), 4.67-4.61 (m, 2 H), 3.68-3.63 (m, 2 H), 2.25-2.00 (m, 2 H), 1.56- 1.44 (s overlaps , 6 H), 0.79 (d, 6 H). EXAMPLE 4 (3ΛS)-N-Cbz-L-Val-L-Leu-N-[3-0-phenylsuIfonyI)-5- methyl-hexa-lE,5-dieneamide The title compound was prepared from N-Cbz-L-Val-OH (available from Bachem) and (3R5)-L-Leu-N-[3-(l -phenyIsulfonyl)-5-methylenehexa-lE,5- dιen]amιde (EXAMPLE 3) using substantially the same procedure as described in EXAMPLE 3 to isolate the desired product as a colorless oil (10 mg). Η NMR (CDCI 3 , 300 MHz) δ 7.89-7.83 (m, 2 H), 7.60-7.5 (m, 3 H), 7.34- 7.35 ( , 5 H), 6.92 (dd, I H), 6.56-6.51 (m, 1 H), 6.36 (m, 1 H), 5.32 (m, 1 H), 5.13- 5.10 ( , 3 H), 4.85-4.75 (m, 3 H), 4.45 (m, 1 H), 3.93 (m, 1 H), 2.35 - 2.10 ( , 2 H), 1.73- 1.47 (m, 7 H), 0.97-0.84 (m, 12 H). EXAMPLE 5 (JΛ5)-N-Cbz-L-Leu-L-Met-N-[3-0 -phenylsuIfonyI)-5-methylhexa -lE,5-dieneamide The title compound was prepared from N-Cbz-L-Leu-L-Met-OH synthesized by solid phase peptide synthesis (or purchased from Bachem) and using (3RS)-]- phenylsi ,f" onyl-3-amino-5-methyl-lE,5-hexadiene hydrochloride (EXAMPLE 2.E) as a starting material in substantially the same procedure described in EXAMPLE 3 (Scheme C) The product was isolated as a colorless oil (10 mg). Η NMR (CDClj, 300 MHz) δ 7.89-7.83 (m, 2 H), 7.60-7.47 (m, 3 H), 7.37- 7.33 (m, 5 H), 6.97-6.90 (m, 2 H), 6.5 (m, 1 H), 5.28-5.23 (m, 4 H), 5.14-5.07 (m, 3 H), 4.52 (m, 1 H), 4.1 (m, 1 H), 2.5 - 1.64 (m overlaps s, 15 H), 0.92 (m, 6 H). EXAMPLE 6 (2S)-2-terl-Butoxycarbonylamino-4-methyl-4-pentenoic Acid A. (25)-2-Amino-4-methyl-4-pentenoyI (S,5)-Pseudoephedrine Amide To a suspension of dry LiCl (4.2 g, 99 mmol) in dry THF (45 L v. as added diisopropylamine (DIA, 4.6 mL, 32.8 mmol) The flask was cooled to -78°C in a dry ice/acetone bath and a solution of n-BuLi (hexanes, 12.7 mL, 31.8 mmol) was added in drops The solution was stirred for 10 minutes, then a solution of (5, )-pseudoephedrine glycinamide ("H", Scheme D; prepared according to Myers et al. J. Am. Chem. Soc. 117: 8488-8489, 1995) (3.6 g, 16.3 mmol) in THF (25 mL) was added in drops over a period of 10 minutes. The reaction mixture was left stirring at -78°C for 20 minutes, changed to an ice bath and stiπed at 0°C for 20 mm 3-Bromo-2-methylpropene (1 8 ml, 17.8 mmol) was added dropwise to the reaction mixture After 0 5 h, 1.0 N HCI (1 10 mL) was added followed by EA (150 mL) The aqueous layer was separated and the EA solution was extracted with 1.0 N HCI (1 10 mL) The combined HCI solution was cooled in an ice bath and the pH adjusted to pH 14 using 50% NaOH The basic solution was extracted twice with CH 2 CI 2 (80 ml each) and the combined CH 2 CI 2 solutions were dried over anhydrous K 2 CO 3 , filtered and concentrated to give a colorless oil that was purified by flash chromatography on silica gel (5% MeOH in CH2CI 2 ) to give a colorless oil (2.95 g, 66%) Η NMR (CDCI 3 , 300 MHz) (mixture of rotomers) δ 7 38-7 27 (m, 5 H), 4 94 -4 78 (m, 2 H), 4 65^ 46 (m, 2 H), 3 91 -3 87 (dd, 0 2 H) 3 79-3 74 (dd, 0 8 H), (m, 1 H), 3.1 1-2 98 (br, 1 H), 2 97 (s, 0 6 H), 2 89 (s, 2 4 H), 2.22- 1 74 (m overlaps s, 7 H), 1.12-1 09 (dd, 2 4 H), 1.01 -1.08 (d, 0 6 H) B. (2S)-2-tert-Bulox\carbonylamino-4-methyI-4-pentenoic Acid To an aqueous solution of 1.0 N NaOH (15.2 ml, 15.2 mmol) was added a solution of (2S)-2-amιno-4-methyI-4-pentenoyl (S.-S -pseudoephedπne amide (EXAMPLE 6 A, above) (2 03 g, 7.6 mmol) in water (15.2 mL) The reaction mixture was stirred under reflux for 1.5 h, and cooled to RT. The crystallized pseudoephedπne was filtered, and the filtrate was diluted with water (75 mL) The aqueous solution was extracted twice with CH 2 C1 2 (150 mL) The combined CH 2 CI 2 solutions were extracted with water (100 mL) and the aqueous solution was washed with CH 2 CI 2 (75 mL) The aqueous solutions were then combined and concentrated under reduced pressure, about 50 mL, solid NaHC0 3 (1.49 g) was added to this aqueous solution followed by p-dioxane (55 mL) The resulting solution was cooled to 0°C and dι- r/-butyl dicarbonate (Boc 2 0, 20 g, 9.17 mmol) was added The reaction was left stirring al 0°C for 1 h, and the temperature was warmed to room temperature and stirred for an additional 0.5 h. The reaction mixture was diluted with water (150 mL) and extracted with EA (i.e., DEA; 150 mL) The EA solution was re-extracted with 2% NaHC0 3 (100 mL) solution. The combined bicarbonate solutions were then acidified to pH 3 using 10% citric acid solution. The acidic solution was extracted three times with EA ( 100 mL). The combined EA solutions were washed with water (2 times; 100 mL each), dried with MgSO, filtered and concentrated to give 1.46 g (84%) of product as colorless oil. Η NMR (CDCI 3 , 300 MHz) δ 9.8 (br, 1 H), 5.3^J.80 (m, 3 H), 4.34-4.31 (m, 1 H), 2.62-2.56 (m, 2 H), 1.76 (s, 3 H), 1.43 (s, 9 H). EXAMPLE 7 (35)-N-Cbz-L-L€u-L-L€u-N-[3-0-phenylsulfonyl)-5- methylhexa-IE,5-dieneamide N-Cbz-L-Leu-L-Leu (Bachem), the (25 2-tert-butoxycarbonylamino-4- methyl-4-pentenoic acid product of EXAMPLE 6.B and diethyl-(phenylsulfonyl)- methyl-phosphonate (EXAMPLE 2.C) were combined using the procedure of EXAMPLES 2 and 3, above, to provide the title compound as a colorless oil. Η NMR (CDCI 3 , 300 MHz) δ 7.86-7.83 (m, 2 H), 7.59-7.46 (m, 2 H), 7. 1 - 7.29 (m, 5 H), 6.95-6.90 (dd, J = 3.9, 1 1 Hz, 1 H), 6.79 - 6.66 (br d, J = 3.9 Hz, 1 H), 6.59-6.56 (m, 2 H), 5.46-5.44 (br m, J = 6.9 Hz, 1 H), 5.14-4.99 (AB q, J = 12.3 Hz, 2 H), 4.84-4.72 (m, 3 H), 4.38^.34 (m, 1 H), 4.13-4.09 (m, 1 H), 2.30-2.03 (m, 2 H), 1.67 (s, 3 H), 1.64-1.25 (m, 6 H), 0.89 - 0.81 (overlapping doublets, 12H). EXAMPLE 8 (3Λ)-N-Cbz-L-Leu-L-Leu-N-[3-(!-phenylsulfonyl)-5 -methylhexa-IE,5-dieneamide The title compound was prepared according to the procedure set forth in EXAMPLE 7, using (2R)-2-tert-butoxycarbonylamino-4-methyl-4-pentenoic acid in place of (25 -2-tert-butoxycarbonylamino -4-methyl-4-pentenoic acid, to afford the desired product as a colorless oil. (2Λ)-2tert- Butoxycarbonylamino-4-methyl- 4-pentenoic acid was prepared according to EXAMPLE 6, above, using (/?,R)-pseudoephedrine glycinamide. EXAMPLE 9 (3 ?S)-4-BenzylpiperidinocarbonyI-L-Leu-L-Leu-N-[3- (1 -pheπylsuIfoπyI)-5-methyIhexa-l E,5-dienelamide K=CH, N A. 4-Benzylpiperidinocarbonyl-L-Leu-OMe To a stirred solution of triphosgene (1.02 g, 3.4 mmol) in anhydrous CH 2 CI 2 (50 mL) was added a solution of L-Leu-OMe (available from Aldrich Chemical Co., Milwaukee, WI) ( 1.8 g, 10.3 mmol) and TEA ( 1.43 ml, 10.3 mmol) in CH 2 C1 2 (25 mL) dropwise over a period of 15 min. (Scheme E). The reaction mixture was stirred at room temperature for 3 h and then a solution of 4-benzylpiperidine ( 1.81 ml, 10.3 mmol) and TEA ( 1.45 mL in anhydrous CH 2 C (25 mL) was added in dropwise. The reaction mixture was then stirred at room temperature for 12 h, concentrated under reduced pressure. The residue was re-dissolved in EA (100 mL) and was washed successively with saturated bicarbonate (50 mL), brine (50 mL), 1.0 N HCI (50 mL) and saturated brine (50 mL), dried over anhydrous MgS0 4 filtered and concentrated to give a colorless oil that was purified by silica gel chromatography (2% MeOH:CH 2 Cl 2 ) to yield the desired product as a colorless oil (2.6 g, 73%). Η NMR (CDCI 3 , 300 MHz) δ 7.24-7.05 (m, 5H), 4.81-4.78 (d, J = 5.1 Hz, 1 H), 4.46-4.39 (m, 1 H), 3.91-3.83 (m, 2 H), 3.63 (s, 3 H), 2.71-2.59 (m, 2 H), 2.48- 2.46 (d, 2 H), 1.65- 1. 40 (m, 6 H), 1. 18 - 1.0 8 (m, 2 H), 0. 8 8 - 0.8 6 (d, 6 H). B. 4-BenzylpiperidinocarbonyI-L-Leu-OH A solution of 4-benzylpiperidinocarbonyl-L-Leu-OMe (EXAMPLE 9.A., above) (2.6 g, 7.5 mmol) in MeOH (60 ml) was cooled to 0°C, LiOH:H 2 0 (1.26 g, 30 mmol) in water (20 mL) was added and the reaction mixture was stirred at 0°C for 2 h and at room temperature for 12 h (Scheme E). The reaction mixture was then concentrated under reduce pressure to 30 ml, diluted with EA (100 ml) and the EA solution was acidified with 1.0 N HCI to pH 1. The organic layer was separated and the aqueous layer was extracted with EA (50mL). The combined EA solutions were washed with water (2 time; 50 mL), dried over anhydrous MgS0 4 filtered and concentrated under reduced pressure to give the desired product as a colorless oil (2.5 g, 99%). Η NMR (CDC1 3 , 300 MHz) 7.32-7.1 1 (m, 5 H), 5.26-5.23 (d, 1 H), 4.53-4.4S (m, 1 H), 3.94-3.89 (m, 2 H), 2.74-2.66 (br t, 2 H), 2.54-2.52 (d, 2 H), 1.86- 1.52 (m, 6 H), 1.32- 1.22 (m, 2 H), 0.93 (d, 6 H). C. 4-Benzylpiperidinocarbonyl-L-Leu-L-Leu-OMe The title compound was prepared using the procedure set forth in EXAMPLE 9. A, above, using Leu-Leu-OMe as a starting material instead of Leu-OMe. The product was isolated as a colorless oil (332 mg, 69%). Η NMR (CDCI 3 , 300 MHz) δ 7.48-7.1 ( , 5 H), 5.28-5.21 (br d, 1 H), 4.61 - 4.40 (m, 2 H), 3.94-3.82 (m, 2 H), 2.71 (t, 2 H), 2.76 (d, 2 H), 1.90-1.69 ( , 9 H). 1.48- 1.34 (m, 2 H), 1.17 - 1.12 (m, 12 H). D. 4-BenzyIpiperdinocarbonyl-L-Leu-L-Leu-OH The title compound was prepared as a colorless oil from the product of 9.C using the procedure of EXAMPLE 9.B. Η NMR (CDCI 3 , 300 MHz) δ 7.34-7.1 1 (m, 5 H), 5.24 (d, 1 H), 4.6 .48 (m, 3 H), 3.94-3.90 (br m, 2 H), 2.70 (br t, 2 H), 2.53 (d, 2 H), 1.71-1.59 (m, 9 H), 1.24-1.10 (m, 2 H), 0.96-0.88 (m, 12 H). E. (3ΛS)-4-BenzylpiperidinocarboπyI-L-Leu-L-Leu-N-[3-(l -phenyl- sulfonyl)-5-methy Ihexa - 1 E,5-dieneamide To a stirred solution of 4-benzylpiperidinocarbonyl-L-Leu-L-Leu-OH (138 mg, 0.31 mmol) in 3 mL of anhydrous CH2CI 2 at room temperature was added HOBt (42 mg, 0.31 mmol), EDC (65 mg, 0.34 mmol), DIEA (107 mL, 0.62 mmol) and 3(RS)-l-phenylsulfonyl-3-amino-5-methyl-lE,5-hexadiene hydrochloride from EXAMPLE 2.E (Scheme E). The reaction mixture was stirred at room temperature for 12 h, diluted with 50 mL of EA, washed with 50 mL of saturated bicarbonate solution, 10% citric acid and water, dried with MgS0 , filtered and concentrated to give crude product that was purified by silica gel chromatography (3% MeOH in CH 2 C1 2 ) to yield 170 mg (81 %) of product as white foamy solid. Η NMR (CDC1 3 , 300 MHz) δ 7.89 - 7.79 (m, 2 H), 7.61-7.45 (m, 3 H), 7.31- 7.1 1 (m, 5 H), 6.95-6.87 ( , 1 H), 6.76-6.72 ( , 1 H), 6.61-6.48 (m, 1 H), 4.96 (d, 1 H), 4.87-4.65 (m, 3 H), 4.35-4.25 (m, 1 H), 4.16-3.80 (m, 3 H), 2.87-2.85 (m, 2 H), 2.65 (d, 302 H), 2.36-2.20 ( . 3 H), 1.79-1.40 (m, 12 H), 1.21- 1.07 (m, 2 H),0.90- 0.79 (m, 12 H). EXAMPLE 10 (3RS) -Tetrahydroisoquinolinylcarboπyl-L-Leu -L-Leu-N-[3-0-phenylsulfony!)-5-methy[hexa-lE,5-dieneamide The title compound was obtained as a glassy solid following the procedure described in EXAMPLE 9.A and 9.B, above, but using 1 ,2,3,4-tetrahydroisoquinoline as a reagent instead of 4-benzylpiperidine (Scheme F). Η NMR (CDCI 3 , 300 MHz) δ 7.85-7.83 (d, 2 H), 7.57-7.44 (m, 3 H), 7.27- Scheme F- 7.13 (m, 5 H), 6.96-6.89 (dd, 1 H), 6.85-6.83 (d, 1 H), 6.60-6.54 (dd , I H), 5.03- 5.01 (d, 1 H), 4.84-1.73 (m, 3H), 4.63^.46 (q, 2 H), 4.36-4.28 (m, 1 H), 4.24-4.18 (m, 1 H), 3.69-3.47 (m, 2 H), 2.89-2.84 (m, 2 H), 1.74-1.72 (d, J = 5.1 Hz, 2 H), 1.70 (s, 3 H), 1.74-1.46 (m, 6 H), 0.97-0.89 (overlapping doublets, 12 H). EXAMPLE 11 (3/ 5)-Tetrahydroisoquinoliπylcarbonyl-L-Val-L-Mel-N- [3- -phenylsulfonyl) -5-methyIhexa-lE,5-dieneamide The title compound was isolated as a colorless oil (100 mg) following the procedure outlined in EXAMPLE 10 (Scheme F), but using L-Val-OMe and L- Met-OMe as reagents (both available from Aldrich Chemical Co., Milwaukee, WI) instead of L-Leu-OMe. Η NMR (CDCI 3 , 300 MHz) δ 7.85-7.80 ( , 2 H), 7.60-7.40 (m, 3 H), 7.19- 7.12 (m, 5 H), 6.75 (dd, 1 H), 6.43-6.32 (m, 1 H), 5.14-4.44 (m, 8 H), 3.97-3.92 (m, 1 H), 3.70-3.50 ( , 2H), 2.87-2.84 (m, 2 H), 2.5-1.95 (m, overlaps s, 10 H), 1. 7 (s, 3 H),0.98-0.83 (m, 6 H). EXAMPLE 12 ( Λ5)-Tetrahydroisoquinolinylcarbonyl-L-Val-L-Leu-N-[3- (1 -pheπylsulfonyI)-5-methylhexa-lE,5-dieneIamide The title compound was isolated as a color less oil (50 mg) following the procedure outlined in EXAMPLE 10 (Scheme F), above, but using L-Leu-OMe as a reagent in place of L-Met-OMe. Η NMR (CDCI 3 , 300 MHz) δ 7.82-7.7 (m, 2 H), 7.55-7.45 (m, 3 H), 7.22- 7.12 ( , 4 H), 7.09-7.01 (m, 1 H), 6.95-6.93 (m, 1 H), 6.62-6.12 (m, 2 H), 5.14^.49 ( , 6 H), 4.36-4.20 (m, I H), 4.0-3.92 (m, 1 H), 3.71-3.53 (m, 2 H), 2.97-2.85 (m, 2 H), 2.49-2.02 (m, 3 H), 1.64- 1.24 ( overlaps s, 6 H), 1.0-0.81 ( , 12 H). EXAMPLE 13 (3S)-4-N-Benzylpiperazinylcarbonyl-L-Leu-L-Leu-N- [3-(l -phenylsulfonyl) hexamide Following the procedure set forth in EXAMPLE 9 (Scheme D), above, substituting 1-benzylpiperazine for 4-benzylpiperidine and substituting (5S)-l-phenylsulfonyl-3-amino-5-methyI-lE,5-hexadiene hydrochloride (e.g., prepared in a manner similar to that set forth in EXAMPLE 7) for (3 ?5)-I-phenylsuIfonyl-3- amino-5-methyI-lE,5-hexadiene hydrochloride. The title compound was isolated as a colorless oil. Η NMR (CD 3 OD, 300 MHz) δ 7.79-7.77 (m, 2 H), 7.60-7.46 (m, 3 H), 7.24- 7.16 (m, 5 H), 6.84-6.77 (dd, J = 5.1, 15 Hz, 1 H), 6.55-6.49 (dd, J = 1.5, 15 Hz, 1 H), 4.46-4.43 (m, 1 H), 4.21-4.17 (m, 1 H), 4.05-4.00 (m, 1 H), 3.40-3.20 (m, 6 H), 2.35- 2.32 (m, 4 H), 1.62-1.39 (m, 8 H), 1.23 - 1.19 (m, 4 H), 0. 8 8-0.7 7 (m, 15 H). EXAMPLE 14 Illustrative In Vitro Assays Summary Overview: Dlustrative methods are described above by which the instant compounds may be synthesized. Testing the intracellular effects of a compound may be accomplished according to cell-based methods disclosed herein, such as those illustrated below using cultured human glioblastoma (HGB) cells stably-transfected with cDNA constructs encoding APP, e.g., the 695 amino acid β- amyloid precursor protein (APP 695 ), as well as other possible truncated forms of APP. Cell-Based Screening Assays: An in vitro system may be used to assay the instant compounds and confirm those that modulate APP:Aβ processing. For instance, the human glioblastoma (HGB) cell line normally secretes only soluble derivatives of APP 5 ι, but APP:Aβ processing may be altered to resemble processing in Alzheimer's disease by stable transfecting the HGB cells with a cDNA construct encoding either: (i) a wild-type 695 amino acid APP (APP 695wI ), or (ii) a 695 amino acid APP containing a "Swedish" double mutation with Asn for Lys and Leu for Met substitutions at codons 670 and 671, respectively, (APP670/6?ι), (codons numbered according to the 770 amino acid APP isoform), or (iii) a 695 amino acid APP containing the 670/671 double mutation and a Phe for Val substitution al codon 717 (APP 67 ( V67 i 7 i 7 )- Altered APP:Aβ processing in the HGB cells may e.g. by determined by collecting conditioned medium from the stably transfected cells and immunobloting with monoclonal antibody specific for an N-terminal sequence in APP (e.g., mAb22Cl), and/or a monoclonal antibody specific for the amino terminus of Aβ (e.g. AbόElO). One or more of the instant compounds are added to the transfected/altered HGB cells and APP:Aβ processing determined by immunobloting with comparison being made between cell cultures, so treated, and untreated control cultures, i.e., using medium collected from the cell cultures and/or cell extracts. M-17 neuroblastoma cells transfected with a mutant APP construct (APP 695NL+ ι) secrete high levels of Aβ and a significant fraction is Aβι^ 2 (39). HGB cells stably-transfected with a construct encoding APP 7067iπi or APP 695N +F 'H secrete detectable levels of an -4 kD peptide, i.e., detectable by immunoprecipitations, SDS-PAGE and/or western blotting. The ability of the instant compounds to modulate APP:Aβ processing in these cells is detected by evaluating Aβ levels in the medium collected from cell cultures or in cell culture extracts. Quantitative assays for Aβ can be used to measure the levels of APP processing to Aβ, both in vitro e.g., in one or more of the cell-based assays, above, and also in extracts of animal tissues or in primary cultures of mixed brain cells (termed mixed brain cultures). For example, immunoblotting of SDS-PAGE gels with polycional rabbit anti-APPws-697 ' fτ ., R369) may used to reveal the different molecular weight species of APP antigens in tissues. Immunoblotting with monoclonal antibody 26D6, specific for amino acid residues 1 -12 of may be used to confirm the presence of Aβ in the tissue extracts. Materials and Methods are set forth following the EXAMPLES section, below. Using such cell-based assays the following results are recorded in vitro: 1. Examples of the instant compounds according to FORMULAS I, II and/or HI, above, decrease processing of APP to Aβ in vitro, i.e., as judged by decreased levels of Aβ in treated HGB cell extracts by ELISA, immunoprecipitation and SDS-PAGE and/or western blotting (TABLE I, next page); 2. The instant compound inhibit Aβ formation in vitro in HGB cells without altering the amount of non-APP proteins (e.g., fϊbronectin, fodrin etc.) synthesized, i.e., as judged by 35 S-biosynthetically radiolabeling proteins synthesized by cells on SDS-PAGE and autoradiography; and 3. The instant compounds inhibited certain cell free cysteinyl proteases in vitro, including Cathepsin S, Calpain L papain, Cathepsin L, but not Chymotrypsin, Cathepsin H, Cathepsin B or Cathepsin C (TABLE n, below). TABLE I the ELIS A methods. Materials and Methods TABLE π Inhibition of Protease Activit In Vitro* • Fluorescent and/or coloπmetnc substrate assays using peptidyl substrates, ND, not determined; Cat, cathepsin, Chymo., chymotrypsin, a) CMPD, compounds as recited in TABLE I, above. EXAMPLE 15 Illustrative Results in Transgenic Animal Models Several useful transgenic animal test models of Alzheimer's disease have been described, e.g Tg2576 and APP-YAC transgenic mice These animal models are useful for determining the modulatory effects of the instant compounds on APP processing to Aβ. For example, the levels of inhibition of Aβ production in vivo may be determined by measuring the levels of Aβ in brain tissue, CSF fluid or plasma using an ELISA, immunoprecipitation and SDS-PAGE and or western immunoblot analyses. Similarly, using APP-YAC homozygous transgenic mice, the instant compounds may be tested to determine whether the) inhibit Aβ production Using such assays the following results may be obtained namely, 1. The instant compounds perferably inhibit Aβ production as judged by decreased plasma or brain tissue levels of Aβ after administration of a tesi dose of one of the instant compounds; and, 2. The instant compounds preferably inhibit Aβ production in brain tissues after administration, i.e., as judged by decreased levels of biosynthetically radiolabeled Aβ in immunoprecipitates from brain tissues. Materials and Methods Cell Lines- The HGB M ^ cell line may be prepared by stably-transfecting human glioblastoma (U138 MG) cells with an APP 9 5 expression plasmid. A human neuroblastoma cell line (IMR-32) is potentially useful as the source for mRNA encoding the sequence of A P < gs cDNA and plasmids cDNA encoding the APP 6 95 may be derived from mRNA puπfied from human neuroblastoma cell line (EMR-32), e g , by RT-PCR amplification followed by cloning into a retroviral construct The DNA fragment containing the APP 695 sequence may be removed from a selected cloned retroviral construct, e g , by partial digestion with endonuclease, and ligated into a mammalian expression vector (e g obtained from Invitrogen, Inc., San Diego, CA.) Aβ Cells Transfection of HGB (or other) cells with the APP 6 95 cDNA (above) may be accomplished using the Lipofectin kit followed by selection of transformaπt clones in G418-contaιnιng medium APP Cells An expression plasmid construct containing APP 6 95 cDNA may be mutated using site-directed mutagenesis in conjunction with PCR to generate an APP 695 plasmid containing missense mutations This approach has been used b) others to yield APP 95 coding region mutations, e g , at codons 670,671 and 717 (codon numbering based upon the APP 770 isoform numbering system), where it has proved useful to generate Asn for Lys, Leu for Met and Phe for Val substitutions, respectively Resulting constructs of this type, e g AP 6 0671 717 may be useful for selecting stably-transfect cell lines Stable cell populations may be subcloned, characteπzed for expression of exogenous APP 695 by immunoblotting with APP specific antibodies, and then selected for use in one or more cell- based assays Antibodies The mouse monoclonal antibody, 26D6, anti-human Aβi ] 2 was prepared by TSD Bioservices 26D6 IgG, 1 e, specific for the N-terrrunus of Aβ, 1 e , Aβj j , was puπfied from ascites by affinity purification on Protein A-Sepharose (Pharmacia) chromatography followed by affinity chromatography on an affinity matrix, (1 e , CnBr- activated Sepharose), containing bound Aβi u, 1 e., at an input concentration of 1 mg/ml resin Affinity puπfied 26D6 was coupled to horse-radish peroxidase (HRP) by Taconic Bioservices (Newark, DE) Rabbit antiserum, i.e., R6257, was raised to ELISA for Aβ An Aβ sandwich ELISA was developed using polyclonal rabbit ntι-Aβι. 0 as a selective capture antibody and HRP-conjugated monoclonal 26D6 (1 e., mouse monoclonal IgG specific for the N-lerminus of Aβ, 1 e., Aβi u, ) for the detect reagent To measure intracellular levels of Aβ and APP, lysates of HGB »swr cells may be prepared, separated by 16% Novcx gradient gels, and immunoblotted with R369, (i.e., rabbit CTF-specific antisera), or the 26D6 monoclonal antibody. For example, APP α- and β-secretase carboxy-terminal products (iα-CTF and iβ- CTF) may be immunoprecipitated with anli-CTF antisera (and Protein A or Protein G Sepharose), immunoprecipitates can be separated by SDS-PAGE, then Aβ detected by western blotting with quantification being achieved using laser scanning densitometry. For detection of Aβ in plasma and CSF, an ELISA assay may be used, e.g., using mouse monoclonal IgG as a capture antibody and biotinylated mouse monoclonal antibody 4G8 (i.e., anti-Aβ 17 . 24 ) as a delect reagent. After washing to remove unbound detect reagent, avidin-HRP is added to generate a colorometric signal in the assay. Treatment Studies and Immunochemical Assays In Vitro: Identical confluent cultures of stably-transfected APP 6 5« or APP 6 7( 6 i 7π cells (approximately 10 7 cells/plate) can be established in 100 mm 3 culture dishes and washed with 5 ml of Ultraculture medium Compounds of interest can be dissolved, e.g., in DMSO, and then diluted using medium As a control, plates can be treated with medium and diluted DMSO vehicle After about 16 h incubation at 37°C with test compound or vehicle, conditioned medium can be collected and clarified, e.g , by lov, speed centπfugation (1000 x g) Clarified conditioned medium (5 ml) samples can then be pre-cleared e.g., using non-immune rabbit sera and Protein A-Sepharose Pre-cleared supematani≤ are immunoprecipitated using e.g a monospecific rabbit anti-Aβ, j* antibody (rpAbl-28) and Protein A-Sepharose. The samples can then be cenlπfuged ( 1000 x g) and the supematants discarded Aβ immunoprecipitates can be solubilized and separated on SDS-PAGE where the separated proteins on the gels can be transferred to nitrocellulose (Hybond) and western immunoblotted using a monoclonal antibody, e.g., 6E10 (Senete , Maryland Heights, MO., ascites fluid diluted 1 :3000) Proteins binding Aβ-antibodies can be identified using biotm-conjugaied goat-anti-mouse IgG (Sigma, St Louis, MO., 1 : 1000) and streptavidin-horseradish peroxidase conjugate ( 1.1000, Amersham, Arlington Heights, IL) The peroxidase activity may be visualized e.g using chemiluminescence (Amersham ECL kit). Compound toxicity may be assessed e.g. using a LIVE/DEAD EukoLight™ Viabi ty/Cytotoxicity assay (Molecular Probes, Inc., Eugene, OR.) according to manufacturer recommended protocols. 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McConlogue, L , Seuben, P., and Sinha, S (1995) J Biol Chem 270: 45 2419-2422 42. Pike, C. J., Burdick, D., Walencewicz, A J., Glabe. C G., and Cotman, C. W (1993) -' Neurosaence 13: 1676- 1687 43 Busciglio, J., Lorenzo, A., Yeh, J., and 50 Yankner, B . A ( 1995 ) in Neuron Vol 14, pp 879-888 44 Meda. L., Cassaiella, M. A., Szendrei, G I., Otvos, L., Baron, P., Villalba, M , FerTari, D., and Rossi, F. (1995) Nature 55 374: 647-650 As will be recognized by those skilled in the art, the various embodiments described herein are provided by way of illustration and not limitation; various modifications and subsiitutions may be made thereto without departing from the spirit and scope of the invention. Such modifications and substitutions are contemplated as within the scope of the following claims.

Claims: WHAT IS CLAIMED IS: I . A compound of FORMULA I, π or HI. or a pharmaceutically acceptable derivative, isostere, mixture or stereoisomer thereof, wherein Ri compπses a W-substituted or unsubstituted lower alkenyl or a lower alkynyl, wherein said W-substituent comprises a halo, a hydroxy, an alkyl, an aryl, a heterocycle, a heteroaryl, an alkoxy, an aminosulfonyl, an alkylcarbonyl, an arylcarbonyl, a heteroarylcarbonyl, a helerocycle-carbonyl, a nitro, a haloalkyl, an amino or aminocarbonyl, X compπses -CH = CH-(CH = CH CH 2 ) or -CH 2 CH 2 -(CH 2 ) 6 , wherein k compπses an integer selected from within the range of 0 to 9, j comprises an integer selected from within the range of 0 to 4, b comprises an integer selected from within the range of 3 to 6; Y comprises S, SO, S0 2 , NR 20 , -N(O)(R 20 ), -PR 2 o, -P(O)(R 20 )-, -P(0)0- or -P(0)(OR 2 o)0, wherein R 2 o comprises either a hydrogen alom or an alkyl or an aryl; Z comprises -(CH 2 ),-A, wherein i is an integer selected from the range of 0 to 4 and A comprises an L- substituted or unsubstituted heterocycle, a heteroaryl or an aryl, and further, wherein said L-subslituent comprises a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, an alkoxy, an aryloxy, a hydroxy, a haloalkyl, a tnfiuoromethyl, a cyano, a nitro, a nitrile, an alkylthio, a phenyl and an -NR30R 31 group and wherein R 30 and R 3 ) each independently comprise H, alkyl, hydroxy or halo lower alkyl; R 2 , R 3 , R« , Rs, R« , R 7 , R«, Q each independently comprise constituents, and n comprises zero or an integer, wherein each of said constituents is selected according to a group selected from among groups (i), (ii), (iii), (iv), (v), (vi) and (vii) as follows: (i) R 3 and R < each independently comprise a side chain of a naturally occurring α-amino acid, a hydrogen atom, an alkyl, an alkenyl, an alkynyl, an aryl, .an aralkyl, an aralkenyl, an aralkynyl, a heteroaryl, a heteroaralkyl, a heteroaralkenyl, a heteroaralkynyl, an L-substituted aryl, an L-substituted aralkyl, an L-substituted aralkenyl, an L-substituted aralkynyl, an M-substituted heteroaryl, an M-substituted heteroaralkyl, an M-substituted heteroaralkenyl or an M-substituted heteroaralkynyl, wherein M comprises a lower alkyl or a halo lower alkyl; R 2 , R. , R«, and R« each independently comprise a hydrogen atom, a lower alkyl, a cycloalkyl or a cycloalkylalkyl; R 7 comprises a C|^, alkyl, an R A RβCH constituent, a aryl, an alkenyl, an alkynyl, a 9-fluorenyl, an aralkyl, an aralkenyl, an aralkynyl, a monocylic or a bicyclic heterocycle or a monocychc or a bicyclic aryl, heteroaryl or aryl -heteroaryl, wherein said aryl, said heterocycle and said heteroaryl groups are optionally substituted with L; Q comprises a -C(O)-, a -O-C(O)-, an -S(0) 2 - or a -HN-C(O)-; n is zero or the integer 1 ; R A comprises a -(T) m -(D) m -R 3 constituent, wherein T is O or NH, D is alkyl or C 2 -« alkenyl, and m is zero or the integer 1; and R B comprises a constituent selected as set forth for R 3 and R 5 ; or alternatively, (ii) R 2 , Rs and R* each independently comprise a constituent as set forth in (i); R 3 and each independently comprise constituents as recited in (i) or (iv), n is zero, and R« and R 7 together with the atoms to which each is attached form a 3- 10 membered heterocyclic moiety containing 1-5 heteroatoms, wherein said moiety is optionally substituted with L; or alternatively, (iii) R 2 , R 3 , R« , R 5 and Rg each independently comprise a constituent as set forth Q compπses a -C(O)-; n compπses the integer 1 ; and Ϊ and R 7 each independently comprise a substituted or unsubstituted carbonyl (-(C=0)-), phenylene, heteroatom, lower alkylene, lower alkylene linked to a heteroatom, wherein said substituent compπses L and also wherein R_<, and R 7 together with the atoms to which they are attached form a cyclic or a bicyclic moiety, or alternatively, (iv) R : , R 5 , Ri, R 7 , R« and Q each independently compπse a constituent as set forth in any of (ι)-(ιn) or (v-vn), and n comprises zero or 1 , R 3 and R each independently comprise a heteroatom or a substituted or unsubstituted lower alkylene or lower alkylene linked to a heteroatom, wherein said substituent comprises L and also wherein R 3 and R4 together with the atoms to which they are attached form a heterocyclic moiety, or alternatively, (v) R 2 , R , Rg, Q each independently compπse a constituent as set forth in (1), and n compπses zero or 1 ; R 3 and R_, each independently comprise a constituent as set forth in either of (1) or (iv), R 5 and R« each independent!) compπse a heteroatom or a substituted or unsubstituted lower alkylene or a lower alkylene linked to a heteroatom, wherein said substituent compπses L and also wherein R 5 and R« together with the atoms to which they are attached form a heterocyclic moiety, or alternatively, (vi) R 2 , R« and R« each independently comprise a constituent as set forth in (i); R 3 and R» each independently comprise a constituent as set forth in either of (i) or (iv), n is zero, and Rs and R each independently comprise a heteroatom or a substituted or unsubstituted lower alkylene or lower alkylene linked to a heteroatom, wherein said substituent comprises L and also wherein R5 and R 7 together with the atoms to which they are attached form a heterocyclic moiety, or alternatively, (vii)R 2 , Rs and R« each independently comprise constituents as set forth in (1), R 3 and R each independently comprise constituents as set forth in either of (1) or (<v); n is O, R« and R 7 each independently comprise a heteroatom or a substituted or unsubstituted lower alkylene or lower alkylene linked to a heteroatom, wherein said substituent comprises L and also wherein R« and R 7 together with the atoms to which each is attached form a 6-12 membered bicyclic heterocyclic or heteroaryl moiet 2. The compound of claim 1 , wherein R 2 , R 3 , R*, Rs, R«, R 7 , Rg, Q wherein the constituents in said groups (ι)-(vn) are further limited as follows, (1) wherein when either of R 3 or Rs comprise an alkyl, each independently comprise a lower alkyl, when R 3 or R 5 comprise an alkenyl, each independently comprises a C 2 10 alkenyl, when R 3 or R 5 comprise an alkynyl each independently comprises a C 2 ^ alkynyl, wherein said M constituent compnses a Ci-* alkyl or a tnfiuoromethyl, when R , R«, R«, or R« comprise an alkyl, each independently comprises a C alkyl, when R 2 , R_t, R«, or Rg comprise an aryl, each independently comprises an L-substituted aryl, when R , R 4 , R*, or Rg compπse a heterocycle each independently comprises an L-substituted heterocycle, when R 2 , R«, R«, or Rs comprise a heteroaryl, each independently comprises an L-substituted heteroaryl, (ii) wherein R<, and R 7 each independently compπse a morphohno, a thiomoφholino, a pyrrolidinyl or a 4-hydroxypyrrolιdinyl; (iii) wherein « and R 7 each independently comprise a succinimidyl, a phthalimidyl or a maleimidyl constituent; (iv) R 3 and R each independently compπse a morphohno, a thiomoφholino, a pyrrolidinyl or a 4-hydroxypyrτolιdιnyl, or alternatively, (v) R 5 and R $ each independently compπse a moφholino, a thiomoφholino, a pyrrolidinyl or a 4-hydroxypyrroIιdιnyl constituent, (vi) R 5 and R 7 each independently compπse a moφholino, a thiomoφholino, a pyrrolidinyl or a 4-hydroxypyrτolιdιnyI, or alternatively, (vii) R« and R 7 each independently comprise 1,2,3,4-letrahydroιsoquιnohnyl. 3. The compound of claim 1 , wherein k and j are 0 and b is 3 or 4. 4 The compound of claim 1 , wherein X compπses -CH = CH-. 5. The compound of claim 1 , wherein Ri comprises a lower alkenyl. 6. The compound of claim 1, wherein Y comprises a SO, an S0 2 , an -N(O)(R 20 ) constituent, a -P(O)(R 20 )- constituent or a -P(0)(OR 2 o)- constituent. 7. The compound of claim 1, wherein Z comprises . an L-substituted or unsubstituted phenyl, pyridyl, pyrazmyl, thienyl, furyl, pyrrolyl, imidazolyl or pyπmidinyl constituent 8 The compound of claim 1 , wherein Y comprises S0 2 -. 9. The compound of claim 1 , wherein X compπses -CH = CH- and v. herein, all constituents are as set forth in claim 1 , but with the provisos that. Y does not comprise NR 20 and A comprises an L-substituted or unsubstituted phenyl, pyridy l, pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl or pyπmidinyl, wherein said L does not comprise aryloxy. 10 The compound of claim 9, with the further provisos in said groups (ι)-(vii) as follows (0 when R 3 or R 5 compπse an alkenyl or an alkynyl, each independently comprises a C 2 .ιo alkenyl or a C 2 ^ alkynyl, and M comprises a C|._ alkyl or a tnfiuoromethyl, (ii) when R 2 , R«, R*, or R« compπse a lower alkyl, each mdependentl) comprises a C|_, alkyl and when R« and R 7 together with the atoms to which each is attached form a heterocyclic moiety, said moiety compπses a moφholino, a thiomoφholino, pyrrolidinyl or a 4-hydroxypyrrolιdιnyl constituent, (iii) when R« and R 7 together with the atoms to which they are attached form a cyclic or bicychc moiety, said moiety comprises a succinimidyl, a phthalimidyl or a maleimidy! constituent; (iv) when R 3 and R 4 together with the atoms to which they are attached form a heterocyclic moiety, said moiety comprises a moφholino, a thiomoφholino, pyrrolidinyl or a 4-hydroxypyrrolιdιnyI constituent; (v) when R s and R* together with the atoms to which they are attached form a heterocyclic moiety, said moiety comprises a moφholino, a thiomoφholino, pyrrolidinyl or a 4-hydroxypyrτolidinyl constituent; (vi) when R 5 and R 7 together with the atoms to which they are attached form a heterocyclic moiety, said moiety comprises a moφholino, a thiomoφholino, pyrrolidinyl or a 4-hydroxypyrτolidinyl constituent; and (vii) when R< and R 7 together with the atoms to which they are attached form a heteroaryl moiety, said moiety comprises a 1,2,3,4-tetrahydroisoquinolinyl constituent. 11. The compound of claim 9, wherein: Ri comprises an unsubstituted lower alkenyl or lower alkynyl and Y comprises SO or S0 2 . 12. The compound of claim 1 1 , wherein Ri comprises an unsubstituted lower alkenyl and Y comprises S0 2 . 13. The compound of claim 12, wherein: Ri comprises 2-methylpropenyl or 2-butenyl; R , R», R« and Rg each independently comprise a alkyl, a lower cycloalkyl or a lower cycloalkylalkyl; R 3 and R« each independently comprise a hydrogen atom, a C 1 - alkyl, a alkylthio-alkyl, an aryl, an aralkyl, a heteroaralkyl, a l-aminobul-4-yl or an aminocarbonyl-CH 2 - constituent; R 7 and (Q)n taken together comprise a acetyl, a benzyloxycarbonyl, an 0-(3-chlorophenyI)-Iactyl, a 9-fluorenylmethylcarbonyl, a Boc, 4-benzylpiperidinocarbonyI, a 4-benzyIpiperazino- carbonyl or 1 ,2,3,4-tetrahydroisoquinolinylcarbonyl; and Z comprises an L-substituted or unsubstituted phenyl. 14. The compound of claim 9, wherein Rj comprises 2-methylpropenyl. 15. The compound of claim 9, wherein: Ri comprises 2-methylpropenyl; R 2 , Rt, R« and Rg each independently comprise a hydrogen atom, a cyclopropyl or a cyclopropyl-methyl; R 3 comprises isobutyl, benzyl, (2-methyIthio) ethyl or isopropyl; R5 comprises an isopropyl or an isobutyl; R 7 and (Q)n taken together comprise benzyloxycarbonyl, 4-benzyIpiperidinocarbonyl, 4-benzylpiperazinocarbonyl or 1,2,3,4- tetrahydro-isoquinolinylcarboπyl; Y comprises S0 2 ; and Z comprises a phenyl or a 4-(3-hydroxy-l-propynyl)phenyl. 16. The compound of claim 1 selected from the group consisting of: N-Cbz-L-Leu-L-Leu-L-Leuene phenyl vinyl sulfone; N-Cbz-L-Leu-L-Leu-D-Leuene phenyl vinyl sulfone; N-(THIQ-carboπyI)-L-Leu-L-Leu-D-Leuene phenyl vinyl sulfone; N-(THIQ-carbonyl)-L-Leu-L-Leu-L-Leuene phenyl vinyl sulfone; N-(TH1Q- carbonyI)-L-Val-L-Met-L-Leuene phenyl vinyl sulfone; N-(THIQ-carboπyl)-L- Val-L-Met-D-Leuene phenyl vinyl sulfone; N-(THIQ-carbonyI)-L-VaI-L-Leu-L-Leuene phenyl vinyl sulfone; N-fTHIQ-carbonyI)-L-Val-L-Leu-D-Leuene phenyl vinyl sulfone; N-(4-benzylpiperidinylcarbonyl)-L-Leu-L-Leu-L-Leuene phenyl vinyl sulfone; N-(4-benzylpiperidinyl-carbonyI)-L ^ Leu-L-Leu-D-Leuene phenyl vinyl sulfone; N-(4-benzyI-piperazinylcarboπyl)-L-Leu-L-Leu-L-Leuene phenyl vinyl sulfone and N-(4-benzylpiperazinyIcarbonyl)-L-Leu-L-Leu-D-Leuene phenyl vinyl sulfone. 17. A pharmaceutical composition comprising one or more compounds of claim 1 , or a pharmaceutically acceptable derivative, isostere, mixture or stereoisomer thereof, in a pharmaceutically acceptable carrier. 18. A pharmaceutical composition comprising one or more compounds of claim 9, or a pharmaceutically acceptable derivative, isostere, mixture or stereoisomer thereof, in a pharmaceutically acceptable carrier. 19. A method of modulating processing of amyloid precursor protein to Aβ in an in vitro culture of cells, comprising the step of administering to said culture of cells the composition of claim 1. 20. A method of modulating processing of amyloid precursor protein to Aβ in an in vitro culture of cells, comprising the step of administering to said culture of cells the composition of claim 9. 21. A method of treating a subject in need thereof to alter processing of amyloid precursor protein to Aβ, comprising the step of administering to said subject the composition of claim 17. 22 A method of treating a subject in need thereof to alter processing of amyloid precursor protein to Aβ, comprising the step of administeπng to said subject the composition of claim 18 23 The method of claim 21 , wherein said subject in need thereof compπses a subject diagnosed as having a neurodegenerative disease selected from among Alzheimer's disease, cognition deficits, Down's Syndrome, Parkinson's disease, cerebral hemorrhage with amyloidosis, dementia pugihstica and head trauma 24 The method of claim 22, wherein said subject in need thereof compπses a subject diagnosed as having a neurodegenerative disease selected from among Alzheimer's disease, cognition deficits, Down's Syndrome, Parkinson's disease, cerebral hemorrhage with amyloidosis, dementia pugihstica and head trauma 25 The method of claim 21 , wherein said subject in need thereof comprises a subject diagnosed as having an autoimmune disease selected from among rheumatoid arthritis systemic lupus erythematosus, Sjogren s syndrome, insulin dependent diabetes 26 The method of claim 22, wherein said subject in need thereof comprises a subject diagnosed as having an autoimmune disease selected from among rheumatoid arthritis, Systemic lupus erythematosus, Sjogren s syndrome, insulin dependent diabetes type I or type π, 27 The method of claim 21 , wherein said subject in need thereof compπses a subject diagnosed as having a traumatic tissue injury, a cardiovascular insufficiency, a stroke, a glucose tissue depπvation syndrome 28 The method of claim 22, wherein said subject in need thereof comprises a subject diagnosed as having a traumatic Ussue injury, , a cardiovascular insufficiency, a stroke, a glucose tissue depπvation syndrome 29. A method for inhibiting the activity of a cysteinyl protease, comprising the step of bringing the cysteinyl protease into contact with a compound of claim 1. 30. A method for inhibiting the activity of a cysteinyl protease, comprising the step of bringing the cysteinyl protease into contact with a compound of claim 9. 31. An article of manufacture, comprising packaging material and a compound of claim 1, contained within the packaging material, wherein said compound is effective to ameliorate or prevent one or more symptoms of a neurological disease, and the packaging material includes a label and a package insert that indicates that the compound is useful for treatment or prevention of said neurological disorder. . 32. An article of manufacture, comprising packaging material and a compound of claim 9, contained within the packaging material, wherein said compound is effective to ameliorate or prevent one or more symptoms of a neurological disease, and the packaging material includes a label and a package insert that indicates that the compound is useful for treatment or prevention of said neurological disorder.

Inventors: MUNOZ BENITO, SRINIVASAN KUMAR, WANG BOWEI, MUNOZ, BENITO, SRINIVASAN, KUMAR, WANG, BOWEI
Applicants: MERCK & CO INC, MUNOZ BENITO, SRINIVASAN KUMAR, WANG BOWEI, MERCK & CO., INC., MUNOZ, BENITO, SRINIVASAN, KUMAR, WANG, BOWEI
Application year: 2000
Main classification: C07K5
IPC codes: A61K31, A61K38, A61P3, A61P5, A61P9, A61P17, A61P19, A61P25, A61P29, A61P37, A61P43, C07C317, C07K5, C12N9