SERINE PROTEASE INHIBITORS COMPRISING alpha -KETO HETEROCYCLES

Abstract: The present invention provides a method of inhibiting the enzymatic activity of a serine protease comprising contacting such protease with an inhibitory amount of a compound of formula (I), wherein Z is a serine protease binding moiety; and R1 is an optionally substituted alkyl, alkenyl, cycloalkyl or aryl group.

Description: SERINE PROTEASE INHIBITORS COMPRISING α-KETO HETEROCYCLES Background of the Invention The serine proteases are a class of enzymes which includes elastase, proteinase 3, chymotrypsin, cathepsin G, trypsin, thrombin, prolyl oligopeptidase and others. A breakdown in the balance of protease/antiprotease activity has been implicated in the pathogenesis of numerous disease states. For example, it is known that many human malignancies are associated with enhanced expression of proteases (Opdenakker et al., Cytokine, 4:251-258 (1992)). These proteases may be involved in growth, chemotaxis, endocytosis, exocytosis, blood coagulation, fibrinolysis and tissue invasion during metastasis of malignant cells (Eisenbrand, Synthesis, 1246-1252 (1996); Kazama, J.B.C. 270:66-72 (1995)). Specifically, plasmin, urokinase- plasminogen activator (uPA) and tissue plasminogen activator (tPA) and a tumor-associated trypsin show a substantial increase in activity in many malignancies. Tumor-associated trypsin has been shown to participate in cancer cell-mediated degradation of extracellular matrix (Koivunen et al., Cancer Research, 51:2107-2112 (1991)) and has been implicated in tumor invasion. Human urinary trypsin inhibitors have been shown to prevent both the intravasation and extravasation step of tumor metastasis (Int. J. Cancer, 63:455-462 (1995)). Urokinase-plasminogen activator and tPA have also been shown to be important in tumor metastasis (Dowell, et al., Cancer Treatment Reviews, 19:283-296 (1993)). A guanidinobenzoatase has been implicated in cancer metastasis, cell migration and tissue remodeling (Poustis-Delpont C. et al., J.B.C, 269:14666-71 (1994); Stevens et al., Br. J. Cancer, 46:934-939 (1982); Ohkoshi et al., J. Max. Fac. Surg., 12:148- 152 (1984); Poustis-Delpont et al., Cancer Research, 52:3622-3628 (1992); Stevens, Biol. Chem., 69:137-143 (1988)). Increased plasmin activity has been directly correlated to increased plasminogen activator activity (Eisenbrand, Synthesis, 1246-1252 (1996)). Compounds capable of inhibiting plasmin, tumor-associated rypsin, guanidinobenzoatase or plasminogen activator represent potential drug candidates for the treatment of the various human malignancies. Hepsin, a membrane associated serine protease, has been shown to activate hum.an factor Nil and to initiate a pathway of blood coagulation on the cell surface leading to thrombin formation (Kazama, J.B.C, 270:66-72 (1995)). It is believed that a variety of neoplastic cells activate the blood coagulation system, causing hypercoagulability and intravascular thrombosis via this and other pathways and that hepsin plays a role in their cell growth, maintenance and morphology (Torres-Rosada et al., Proc. Natl. Acad. Sci. USA, 90:7181-7185 (1993)). Hepsin is present at elevated levels in regions of active cell proliferation in animal models and anti-hepsin antibody has been shown to suppress the growth of human hepatoma cells in culture. Hepsin is also suspected to be a physiological inactivator of the tumor suppressor protein maspin. Chymase is believed to be responsible for angiotensin I converting enzyme (ACE) independent activation of angiotensin II in the heart (Urata, et al., J.B. C, 265 :2963-2968 (1997)). This event appears to play a role in the hypoxic or ischemic heart (Urata, et al., Am. J. Hypertens., 9:277-284 (1996)). In addition, in the failing or compromised heart, human chymase is believed to be responsible for an alternate production of angiotensin II, which has been shown to take place in the presence of angiotensin converting enzyme (ACE) inhibitor. A cause and effect relationship has been shown between endogenous vascular elastase (ENE) and experimentally induced pulmonary hypertension in experimental animal models (Zhu, et al., J. Clin. Invest., 94:1163-1171 (1994)). Pulmonary hypertension is commonly associated with congenital heart defects, pulmonary diseases associated with chronic hypoxia, hepatic disorders and connective tissue disease. Increased pulmonary artery elastolytic activity associated with the monocrotaline-induced pulmonary hypertension model has been shown to be moderated by treatment with an elastase inhibitor (Ye, et al., Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H1255-H1267 (1991); Cowan et al., J. Clin Invest., 97:2452-2468 (1996)). In some models, early inhibition of ENE activity largely prevented pulmonary vascular damage. Although, ENE has been shown to be sensitive to leukocyte elastase (LE) inhibitors, it is believed that it is a novel enzyme distinct from LE. Inhibitors of ENE may be useful in treating pulmonary vascular disease in infants, restenosis secondary to angioplasty, pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis after cardiac transplant, post-cardiac tr.ansplant coronary arteriopathy, atherosclerosis and reperfusion injury following myocardial infarct. Prolyl oligopeptidase degrades oxytocin, neurotensin, substance P, thyrotropin releasing hormone, bradykinin, angiotensin II and vasopressin (U.S. patent 5,506,256; Tsutsumi, et al., J. Med. Chem., 37:3492-3502 (1994)). It is also believed to degrade amyloid precursor protein, and therefore is suspected to play a role in Alzheimer's disease. Aprotinin, a pancreatic basic trypsin inhibitor, was first described by H. Kraut et al. in 1930 (J. Physiol. Chem., 192:1 (1930)). Aprotinin has been studied and characterized extensively over the last few decades. It is the active ingredient of Trasylol ® (Miles Laboratories), a drug which is marketed for the treatment of diseases such as hyperfibrinolytic hemorrhage and traumatic-hemorrhagic shock, or acute pancreatitis. Aprotinin has been shown to be an inhibitor of serine proteases (Fritz et al., Drug Res. 33 (I):479-494 (1983)), .and is considered to be a broad-specificity inhibitor. In addition to trypsin and chymotrypsin, aprotinin inhibits plasmin and several kallikreins. It is also used prophylactically to reduce perioperative blood loss and to reduce the need for blood transfusions, mainly in patients undergoing coronary artery bypass graft surgery. Although aprotinin is generally well tolerated, its main adverse side effects include increased incidence of postoperative renal dysfunction and allergic reactions, in some cases leading to anaphylaxis, which has in some cases been fatal. Patients who have had prior exposure to aprotinin are at higher risk for anaphylaxis. These two main adverse effects are both due to the properties of aprotinin as a protein, problems which may be overcome with a small, low molecular weight, synthetic drug with a similar inhibition profile as aprotinin. Additionally, new synthetic drugs would eliminate the need for extracting aprotinin from bovine lung or for its combinatorial expression. It is clear that a need exists for methods of treating and/or preventing serine protease mediated pathologies. Summary of the Invention The present invention provides methods of inhibiting the enzymatic activity of serine proteases comprising contacting such protease or proteases with an inhibitory amount of a compound of formula (I): (I) wherein Z is a serine protease binding moiety; Rj is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxy; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C 5 - C 12 )aryl, (C 5 -C 12 )arylalkyl or (C 5 -C 12 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; and X and Y are independently O, S or N, said N being optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C 5 -C 6 )aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; wherein at least one of X or Y is N. It will be understood that where X or Y is substituted N, both X and Y are N. In one embodiment, Ri is methyl, dimethylamino, phenyl or benzyl optionally substituted with methyl, halo, methylenedioxy, methoxy, dimethoxy, trimethoxy, trifluoromethyl and dimethylamino. According to several preferred embodiments, X is O and Y is N; X is N and Y is O; or both X and Y are N. In a preferred embodiment, Z is of the formula (II): R, R, (II) wherein AA,, AA 2 , AA 3 , AA 4 and AA 5 are independently an amino acid residue or amino acid residue mimetic; a direct bond or absent; and R 4 and R 4 ' are independently -C(O)R 5 , -C(O)NHR 5 , -S(O) 2 R 5 , -C(O)OR 5 , -C(O)-(C 5 - C 6 )aryl-C(O)-R 5 , -CR 5 or R 5 , where R 5 is H, alkyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, hydroxy, alkoxy, haloalkyl, amino, aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy or alkylcarboxamide; cycloalkyl, alkylcycloalkyl, (C 5 -C 12 ) aryl or (C 5 -C, 2 )arylalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, alkoxy, haloalkyl, amino, . aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkyl, alkenyl, alkynyl or (C 5 -Cι 2 )aryl; or absent; or together R 4 and R 4 ' form a ring comprising 5-7 atoms selected from C, N, S and O. Thus, preferably, Z comprises a pentapeptidyl, tetrapeptidyl, tripeptidyl or dipeptidyl binding moiety. Preferably, the amino acids are selected from arginine or an arginine mimetic; proline; aspartic and glutamic acid and the aryl and alkyl esters thereof; alanine and glycine optionally substituted at the α-carbon or α-nitrogen with alkyl, cycloalkyl or aryl; leucine, isoleucine; cysteine optionally substituted at the sulfur atom with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydro-phenylalanine, indoline-2- carboxylic acid; tetrahydroisoquinoline-2-carboxylic acid optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tyrosine, serine or threonine optionally substituted with alkyl or aryl; tryptophan, histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysine optionally substituted at the nitrogen atom with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or cycloalkyl, bicycloalkyl, cycloalkyl alkyl, bicycloalkyl alkyl or fused aryl-cycloalkyl alkyl optionally comprising 1 or more heteroatoms selected from N, O and S. Alternatively, AA, may be described by the formula (Ilia): (IHa) wherein X' is CR 2 ' or N; and R 2 , R 2 ' and R 2 " are independently H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxy, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or - RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C 5 -C 6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl- oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C 5 -C 12 ) aryl, (C 5 -C 12 )arylalkyl or (C 5 - C 12 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with hydroxy, halo, cyano, keto, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; or R 2 and R 2 ' together with X', where X' is C, form a ring comprising 4-7 atoms selected from C, N, S and O, said ring optionally substituted with hydroxy, halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkyl amidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, - O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio. Similarly, AA 2 may be described by the formula (Illb): (Illb) or alternatively selected from a mimetic of formulas IN to XXIN: wherein X" is CR' 3 or N; R 3 , R' 3 and R" 3 are independently H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxy, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or - RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C 5 -C 6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl- oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C 5 -C I2 ) aryl, (C 5 -C, 2 )arylalkyl or (C 5 - C I2 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with hydroxy, halo, cyano, keto, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; m is 0, 1 or 2; n is 0, 1 or 2; G is -C(O)-, -NHC(O)-, -S(O) 2 -, -OC(O)-, -C- or a direct bond; Rg, R 7 , R' 6 , R' 7 are independently H, alkyl, alkenyl, halo, alkoxy, carboxyl, carboalkoxy, amino, aminoalkyl, dialkylamino; cycloalkyl, (C 5 -C 6 ) aryl or (C 5 -C 6 ) arylalkyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, guanidine, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine; and U, V, W and Y' are independently or together N, C, C(O), N(Rα) where Ro is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, S and N, and optionally substituted with halo or alkyl; N(R, 0 ) where R l0 is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fused aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, guanidine, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine; or C(R n )(R 12 ) where R n and R 12 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with gu.anidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine. AA 3 , AA 4 and AA 5 may be either a direct bond or absent; or, where an amino acid, preferably selected from arginine or an arginine mimetic; proline; aspartic and glutamic acid and the aryl and alkyl esters thereof; alanine or glycine optionally substituted at the α-carbon or α-mtrogen with alkyl, cycloalkyl or aryl; leucine, isoleucine; cysteine optionally substituted at the sulfur atom with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydro-phenylalanine, indoline-2-carboxylic acid; tetrahydroisoquinoline-2-carboxylic acid optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tyrosine, serine or threonine optionally substituted with alkyl or aryl; tryptophan, histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysine optionally substituted at the nitrogen atom with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or cycloalkyl, bicycloalkyl, cycloalkyl alkyl, bicycloalkyl alkyl or fused aryl-cycloalkyl alkyl optionally comprising 1 or more heteroatoms selected from N, O and S; According to one embodiment, X' is N. In another embodiment, X" is N. Preferably, X' is CR' 2 and X" is CR' 3 , where R' 2 and R' 3 are H. Where the present method is used to inhibit thrombin, preferably AA, is Arg or an Arg mimetic. In one embodiment, X' is CR' 2 and R 2 is alkyl or alkenyl substituted with guanidinyl, amino or amidylguanidine; benzyl optionally substituted with amidine; alkylpyridine, alkylamino pyridine; alkylimidazole or alkylaminoimidazole substituted with amino; or alkylcyclohexane, said hexane ring optionally comprising 1 or more nitrogen atoms and optionally substituted with 1 or more keto and/or amidine groups. More specifically, according to this embodiment, R 2 is -CH 2 (CH 2 ) 2 NHC(=NH)NH 2 ; -CH 2 (CH 2 ) 4 NH 2 ; benzylamidine; -CH 2 (CH 2 ) 2 NH-pyridine; -CH 2 NHC(O)NHC(=NH)NH 2 ; -CH 2 CH 2 CH 2 -(imidazole)-NH 2 ; -CH 2 CH 2 NH-(imidazole)- NH 2 ; or -CH 2 -(N,N-diketocyclohexane)-C(=NH)NH 2 ; or alternatively represented by the following: In one preferred embodiment, AA 2 is Gly. Where the target serine protease is plasmin, preferably AA, is Arg or Arg mimetic; Lys or Orn; and more preferably Lys. In a further preferred embodiment, Z is R 4 -Pro-Phe- AA,-. Where the serine protease is trypsin, preferably AA, is Arg or Lys. In one embodiment, the serine protease is plasma kallikrein, where preferably Z is R 4 - AA 3 -AA 2 -AA,.-; where AA ! is Arg, Arg mimetic or Lys; AA 2 is Phe, Met or Leu; and AA 3 is Pro. In another embodiment, the serine protease is tissue kallikrein, and preferably Z is R 4 - AA 4 -AA 3 -AA 2 -AA,-; where AA, is Arg or Arg mimetic; AA 2 is Leu or Phe; AA 3 is Arg, Arg mimetic or Pro; and AA 4 is Thr. The methods of the present invention may also be used to inhibit the protease guanidinobenzoatase, where preferably AA, is Arg or Arg mimetic; or a guanidinobenzoyl containing moiety. In addition, the methods may be used to inhibit chymase, where preferably Z is R 4 - where AA, is Tyr, Phe, Trp or Leu. In a preferred embodiment, AA 2 is Pro; AA 3 is His; AA 4 is He; and AA 5 is Tyr. Alternatively, AA 2 is a mimetic of formulas IN to XXIN. Where the serine protease is mast cell tryptase, preferably Z is R 4 -AA 3 -AA 2 -AAi-; where AA, is Arg or Arg mimetic; AA 2 is Gly, Nal, Arg, Arg mimetic, Leu or Phe; and AA 3 is Leu, Arg, Arg mimetic, Lys, Ser or Phe. Where the serine protease is prolyl oligopeptidase, preferably AA, is Pro. In addition, the methods may be used to inhibit viral serine proteases such as hepatitis C virus ΝS3 polyprotein endopeptidase, where Z is preferably R 4 -AA 4 -AA 3 -AA 2 -AA,-; where AA, is Cys; AA 2 is Cys or Ala; AA 3 is Nal; and AA 4 is Nal. Where the serine protease is human cytomegalovirus protease, preferably Z is R 4 - AA 4 -AA 3 -AA 2 -AA,-; where AA, is Ala; AA 2 is Asn, Asp, Gin, Glu or Lys, or selected from their derivatives or esters; AA 3 is Val, He or Leu; and AA 4 is Nal. The methods may also be used to inhibit assemblins, where preferably Z is R 4 -AA 4 - AA 3 -AA 2 -AA,-; where AA, is Ala; AA 3 is Leu, Nal or lie; and AA 4 is Tyr; and preferably AA 2 is Gin or Lys, or their derivatives. Where the serine protease is u-plasminogen activator, preferably Z is R 4 -AA 4 -AA 3 - AA 2 - AA,-; where AA, is Arg, Arg mimetic or Lys; AA 2 is Arg or Arg mimetic, Lys or a derivative thereof, or Gly; and AA 3 is Ser; and preferably AA 4 is Gly. Where the serine protease is t-plasminogen activator, Z is preferably R 4 -AA 3 -AA 2 - AA,- where AA, Arg, Arg mimetic or Lys; AA 2 is Arg or Arg mimetic, Lys or a derivative thereof, Gly or Ala; and AA 3 is Arg or Arg mimetic. The methods may also be used to inhibit Schistosoma serine proteases. The present invention further provides the following novel inhibitors: Ν-[Ν-(4-phenyl-l-ketobutane)-(L)-prolyl]-2-(S)-[(3-(3-phenylpropane)-l,2,4- oxadiazolyl)-ketomethane]-pyrrolidine (CQ-0006); N-(Benzyloxycarbonyl)-L-valyl-N-[l-[3-[5-(2,6-difluorobenzyl)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide (CE-2036); N-(Benzyloxycarbonyl)-L-valyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide (CE-2048); N-(Benzyloxycarbonyl)-L-valyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-N-benzylglycinamide (CE-2056); N-Succinyl-L-valyl-N-[ 1 -[3-[5-(3-trifluoromethylbenzyl)- 1 ,2,4- oxadiazolyl] carbonyl] -2-phenylethylenyl] -L-prolinamide (CE-2061 ); N-[4-(4-Morpholinylcarbonyl)benzoyl]-L-valyl-N-[ 1 -[3-[5-(3- trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L- prolinamide (CE-2064); N-Acetyl-L-alanyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide (CE-2081); N-(Benzyloxycarbonyl)-L-valyl-N-[l -[2-[5-(3-methylbenzyl)- 1 ,3,4- oxadiazolyl]carbonyl]-l-methylethyl]-L-prolinamide (CE-2083); N-(B enzyloxycarbonyl)-L-t-butylglycyl-N- [ 1 - [3 - [5-(3 -trifluoromethylbenzyl)- l,2,4-oxadiazolyl]carbonyl]-2-methylpropyl]-L-prolinamide (CE-2093); N-(Benzyloxycarbonyl)-L-Nalyl-N-[l-[3-[5-(naphthyl-2-methylene)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide (CE-2152); N-(Benzyloxycarbonyl)-L-TIC-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-Methylpropyl]-L-prolinamide (CE-2183); N-(3-Pyridylcarbonyl)-L-Nalyl-N-[l-[3-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-(S)-Methylpropyl]-L-prolinamide (CE-2161); N-(Methanesulfonyl)-L-valyl-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide (CE-2163); N-(Phenylsulfonyl)-L-valyl-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide (CE-2168); N-(3-Pyridylcarbonyl)-L-valyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)-l,2,4- oxadiazolyl] carbonyl] -2-(S)-methylpropyl] -L-prolinamide (CE-2171 ) ; N-(4-Pyridylmethyleneoxycarbonyl)-L-valyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide (CE-2185); N-(4-Pyridylmethyleneoxycarbonyl)-L-valyl-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide (CE-2186); and N-(Pyrrolyl-2-carbonyl)-L-valyl-N-[ 1 -[2-[5-(3-methylbenzyl)- 1 ,3,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-N-(l-indanyl)glycinamide (CE-2195). The compounds described herein may also be used as research and diagnostic tools, as coatings adsorbed or covalently attached to the surfaces of medical equipment and instruments such as bypass pumps, catheters and tubing, and as preservatives of transplantation tissues and organs. As used herein, the term "serine protease binding moiety" means a chemical group capable of binding to the substrate binding site of a serine protease, typically defined in the literature as the S,-S n site. The term includes both peptides and peptide mimetics. Preferably, the binding moiety is selected such that when linked to the keto-heterocycle, the moiety provides the resulting compound with inhibitory activity against the target serine protease of less than 100 μM (I , value); and more preferably of less than 10 μM. As used herein, the term "optionally substituted" means, when substituted, mono to fully substituted. As used herein, the term "independently" means that the substituents may be the same or different. As used herein, the term "alkyl" means C,-C 15 , however, preferably C,-C 7 . As used herein, the term "alkenyl" means C,-C, 5 , however, preferably C,-C 7 . As used herein, the term "alkynyl" means C,-C, 5 , however, preferably C,-C 7 . It will be understood that alkyl, alkenyl and alkynyl groups, whether substituted or unsubstituted, may be linear or branched. As used herein, the term "aryl," unless otherwise stated, means aryl groups preferably comprising 5 to 12 carbons, and more preferably 5 to 6 carbons. Unless otherwise indicated, the term aryl includes mono-and bi-cyclic, as well as fused ring systems, including aryl- cylcoalkyl ring systems. As used herein, the term "arylalkyl" includes mono-substituted alkyl groups (e.g., benzyl), as well as di-substituted alkyl groups such as -alkyl(phenyl) 2 (e.g., -CH(phenyl) 2 ). As used herein, where the term ".arylalkyl" or "arylalkenyl" is defined by the general formula (C x -C y )arylalkyl or (C x -C y )arylalkenyl, x and y refer to the number of carbons making up the aryl group. The alkyl group is as defined above. As used here, the term "arylalkenyl" includes aryl compounds having an alkenyl chain comprising 1-3 or more double bonds. Exemplary arylalkenyl groups include =CH-CH 2 -aryl and -CH=CH-aryl, where aryl is preferably phenyl. As used herein, the term "arginine mimetic" means an amino acid residue with a side chain substituent of the formula -R'-C(= + NH 2 )NH 2 ; -R'-NHC(= + NR")NR°; or -R'-NR"R° where R' is cycloalkyl, aryl or arylalkyl optionally substituted with one or more heteroatoms selected from N, S or O; and R" and R° are alkyl or cycloalkyl. As used herein, the term "Cbz" means benzyloxycarbonyl; and the term "Mu " means morpholino. Pharmaceutically acceptable salts of the compounds described above are within the scope of the invention. Detailed Description of the Invention Peptidyl inhibitors of elastase comprising elastase binding moieties and certain keto- heterocycles have been previously described in the parent and grandparent applications of the present application (see also, WO 96/16080, incorporated herein). It has been surprisingly found that compounds comprising these keto-heterocycles are highly potent and specific inhibitors of a wide variety of other serine proteases as well. The inhibiting activity can be directed against any serine protease by identifying the binding moiety specific for that protease. The characteristics for the P, . . . P n residues (using substrate nomenclature by Schechter and Berger (Biochem. Biophys. Res. Commun. 27: 157 (1967); Biochem. Biophys. Res. Commun. 32: 898 (1968)), which define the minimum recognition sequence of enzymes for small synthetic peptide substrates or inhibitors are known for many enzymes or can be determined by measuring rates of hydrolysis of various substrates. For example, inhibitors may be designed based on the aprotinin binding profile, where the binding moieties may comprise Pro-Phe in the P3-P2 positions, and Arg or an Arg mimetic, Lys or Orn in the PI position. For plasmin, Lys is preferred over Arg or its mimetic in the PI position. Such inhibitors may be used to treat coagulation disorders. Where the target protease is trypsin, Arg or an Arg mimetic is again preferred over Lys in the PI position. Such inhibitors may be effective in treating, for example, pancreatitis. Substrates of plasma kallikrein, which acts on kininogen to release kallidin and activates Factor XII, typically have Arg or Lys in the PI position, although Arg is again preferred; bulky residues are preferred for P2, such as Phe, Met or Leu; and Pro is tolerated in P3 (Hibino et al., J Invest. Dermatol. 90:505-510 (1988); Page et al., J.B.C 266:8142-8148 (1991)). Tissue kallikrein prefers Arg in PI; whereas bulky or negative residues are preferred in P2, such as Leu and Phe; Arg or Pro (with Arg preferred) in P3; and Thr in P4 (Hibino et al, J Invest. Dermatol. 90:505-510 (1988); Page et al, J.B.C 266:8142-8148 (1991)). Guanidinobenzoatases prefer Arg, Arg mimetics or guanidinobenzoyl containing moieties in the PI. Such inhibitors may be used, for example, to inhibit cancer cell growth. Thrombin, which hydrolyzes fibrinogen to form fibrin and release fibrinopeptides, prefers Arg in PI and Gly in P2. Inhibitors may be used, for example, to treat coagulopathies. For chymase, Tyr and Phe are preferred in PI although Trp and Leu are accepted. Where the substrate or inhibitor is truncated, there is a strong preference for Pro in P2. In addition, His is preferred in P3, He in P4 and Tyr in P5. Inhibitors of chymase may be used, for example, to treat hypertension as well as progressing myocardial deterioration. Mast cell tryptase, which acts on vasoactive octaicosapeptide, fibrinogen and fibronectin and other substrates, prefers Arg in PI; Gly in P2, although Nal, Arg, Leu and Phe are also accepted; and Leu or Arg in P3, while Lys, Ser and Phe are also acceptable. Inhibitors may be used to treat asthma, allergies, arthritis, cutaneous mastocytosis and psoriasis (Tanaka et al., J.B.C, 258:13552-13557 (1983); Caughey, Am. J. Respir. Crit. Care Med. 150:S138-S142 (1994)). Prolyl oligopeptidase prefers Pro in PI (Yoshimoto et al., J.B.C, 255:4786-4792 (1980); Tsutsumi et. al, J. Med. Chem., 37:3492-3502 (1994); U.S. patent 5,506,256). Inhibitors may be used, for example, to treat Alzheimer's disease. Hepatitis C virus ΝS3 polyprotein endopeptidase is specific for Cys in PI; prefers Cys over Ala in P2; and Nal in P3 and P4 (Steinkuehler et al., J. Virology, 70:6694-6700 (1996)). Inhibitors may be used to treat hepatitis C infections. Human cytomegalovirus protease, which is responsible for production of mature virions and processing of viral assembly protein precursors, prefers small residues in PI, such as Ala; Asn, Asp, Gin, Glu or Lys in P2; Nal, He or Leu in P3; and Val in P4 (Chen et al., Cell, 86:835-843 (1996); Tong, et al., Nature, 383:272-275 (1996)). Assemblins (HSNI protease and HSNII protease) or Herpesvirus assemblin prefer Ala in PI ; are flexible with respect to P2, although Gin or Lys are preferred; Leu is preferred over Nal and He in P3; and Tyr in P4. Inhibitors may be used to treat Herpes virus infections. In the case of u-plasminogen activator, which hydrolyzes plasminogen to form plasmin primarily in migrating cells, Arg is preferred over Lys in PI; Gly in P2; Ser in P3; and Gly may be preferred in P4. Inhibitors may be used to inhibit cancer invasion and metastasis, and to treat stroke (Lindgren, Stroke, 27:1066-1071 (1996); Opdenakker et al., Cytokine, 4:251-258 (1992)). For t-plasminogen activator, which hydrolyzes plasminogen to form plasmin primarily in endothelial cells, Arg is preferred in PI, although Lys may be tolerated; Gly is preferred over Ala in P2; while Arg is required in P3 for uPA vs. tPA specificity. Indications include angiogenesis and neovascularization in cancer, and stroke (Lindgren, Stroke, 27:1066-1071 (1996); Opdenakker, et al., Cytokine, 4:251-258 (1992); Coombs, J.B.C, 271:4461-4467 (1996)). In addition to altering the binding moiety Z, the substituent on the heterocycle (i.e., R,) can be varied to further increase the specificity of these compounds toward the desired serine protease. Preferred R, substituents include methyl, dimethylamino; phenyl or benzyl optionally substituted with methyl, halo, methylenedioxy, methoxy, dimethoxy, trimethoxy, trifiuoromethyl and dimethylamino. In addition, the heterocycle's heteroatoms can be varied to enhance the activity of the compound. Preferably, the heterocycle is a 1,2,4-oxadiazole, 1,3,4-oxadiazole or a 1,2,4-triazole. The compounds of the present invention, salts thereof, and their intermediates can be prepared or manufactured as described herein or by various methods known in the chemical art, as well as by extension and modification of methods previously described (see, for example, WO 96/16080). An alternative method may be used where suitably protected peptides are converted by the action of an activating coupling reagent such as BOP-C1 or HBTU to a Weinreb amide. For a inhibitor comprising a 1,3,4-oxadiazole heterocycle, the Weinreb amide is then reacted with a 5-substituted 2-lithio- 1,3,4-oxadiazole at appropriate temperatures ranging from -78 °C to -25 °C in a suitable solvent such as THF or ether to provide the desired keto-oxadiazoles in a single step. Protecting groups, if present, are then removed to provide the enzyme inhibitors in an efficient and convergent manner. A number of efficient methods to synthesize 5-substituted 1,3,4-oxadiazoles are known in the art. Conveniently, these compounds can be synthesized in a single step by refluxing hydrazides of common carboxylic acids with excess ethyl orthoformate at high temperature. The excess orthoformate is hydrolyzed in the workup and the 5-substituted 1,3,4-oxadiazoles are often obtained in essentially pure form without further purification necessary. The method is illustrated in general form in scheme 1 below. Scheme 1. , where AA„ means AA 2 . . . AA 5 . The compounds described herein are useful in inhibiting the activity of serine proteases, by contacting the compound with the targeted protease, either in an in vivo or an in vitro environment. As used herein, the term "contacting" means directly or indirectly causing the inhibitor and the protease to come into physical association with each other. Contacting thus includes physical acts such as placing the inhibitor and protease together in a container, or administering the inhibitors to a patient. Thus, for example, administering a compound of the invention to a human patient evidencing a disease or disorder associated with abnormal and/or aberrant activity of such proteases in a method for inhibiting the enzymatic activity of such proteases which are associated with disease or disorder, falls within the scope of the definition of the term "contacting." Pharmaceutically acceptable salts of serine protease inhibitors described herein may also be used in practicing the methods of the present invention. The term "pharmaceutically acceptable salts" as used herein includes organic and inorganic acid addition salts such as chloride, acetate, maleate, fumarate, tartrate and citrate. Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt or potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt. Examples of pharmaceutically acceptable ammonium salts are ammonium salt, trishydroxymethylaminomethane and tetramethylammonium salt. Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine and phenylalanine. Although the compounds described herein and/or their salts may be administered as the pure chemicals, it is preferable to present the active ingredient as a pharmaceutical composition. The invention thus further provides the use of a pharmaceutical composition comprising one or more compounds and/or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and or prophylactic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Pharmaceutical compositions include those suitable for oral, topical or parenteral (including intramuscular, subcutaneous and intravenous) administration. The compositions may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combination thereof, and then, if necessary, shaping the product into the desired delivery system. Pharmaceutical compositions suitable for oral administration may be presented as discrete unit dosage forms such as hard or soft gelatin capsules, capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or as granules; as a solution, a suspension or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art., e.g., with enteric coatings. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservative. The compounds may also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampules, pre-filled syringes, small bolus infusion containers or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. For topical administration to the epidermis, the compounds may be formulated as ointments, creams or lotions, or as the active ingredient of a transdermal patch. Suitable transdermal delivery systems are disclosed, for example, in Fisher et al. (U.S. Patent No. 4,788,603) or Bawas et al. (U.S. Patent No. 4,931,279, 4668,504 and 4,713,224). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The active ingredient can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122, 4,383,529, or 4,051,842. Compositions suitable for topical administration in the mouth include unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier. When desired, the above-described compositions can be adapted to provide sustained release of the active ingredient employed, e.g., by combination thereof with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic polymer gels or mixtures thereof. The pharmaceutical compositions according to the invention may also contain other adjuvants such as flavorings, coloring, antimicrobial agents, or preservatives. The compositions may also be administered via inhalation, using a suitable delivery vehicle. It will be further appreciated that the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg/day, e.g., from about 1 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day. The compound is conveniently administered in unit dosage form; for example, containing 0.5 to 1000 mg, conveniently 5 to 750 mg, most conveniently, 10 to 500 mg of active ingredient per unit dosage form. Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 μM, more preferably, about 1 to 50 μM, most preferably, about 2 to about 30 μM. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 0.5-500 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/Tir or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s). The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. The inhibitors described herein may be also used for the detection and quantification of the activity of a serine protease in a pure sample, mixture or biological fluid or tissue. The activity can be measured with a protease substrate in the absence and presence of a known concentration of the inhibitor. Specific inhibitors can also be used to confirm that the observed activity is due to a particular protease. The inhibitors described herein may also be used to identify and purify serine proteases. The inhibitors can be covalently linked to a solid support, such as an affinity column or beads used in batch methods, and used to purify a protease or enrich a mixture containing the protease. The inhibitor may be linked to the solid support or bead either directly, via a linker of variable length such that linkage does not interfere with the binding properties (see, e.g., Thornberry, N., Methods in Enz., 244:615-31 (1994)). Alternatively, the inhibitor may be covalently linked to biotin and arrayed on a solid support via avidin/biotin interaction. The present invention further provides a method of reducing perioperative blood loss by introducing an inhibitor into a patient directly, or by pretreating, coating or priming medical equipment and devices such as bypass pumps, tubes and catheters, with a suitable liquid composition, or whole blood, comprising one or more inhibitors described herein. Such compositions may also be used to preserve tissues and organs used in transplantation. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims. The following examples are given to illustrate the invention and are not intended to be inclusive in any manner: Examples Example I - Synthesis of N-[N-(4-phenyl-l-ketobutane)-(L)-prolyl]-2-(S)-[(3-(3- phenylpropane)- 1 ,2,4-oxadiazolyl)-ketomethane]-pyrrolidine (CQ-0006). A. N-Benzyloxycarbonyl-2-(S)-(2-acetoxyethanamide oxime)-pyrrolidine hydrochloride. To a mixture of N-benzyloxycarbonyl-2-(S)-(2-acetoxy-ethanenitrile)-pyrrolidine (110.52 g, 0.37 mol) dissolved in 1000 ml of ethanol and 250 ml of water was added hydroxylamine hydrochloride (33.0 g, 0.47 mol), and sodium acetate (45.0 g, 0.55 mol). This mixture was then heated with the temperature maintained between 40-50°C. After 3 hrs. the reaction mixture was concentrated and the residue taken up in ethyl acetate and washed with water. The organic layer was then dried (anhydrous magnesium sulfate), and the solvent evaporated. This material was then converted into its hydrochloride salt (89.23 g, 66%). B. 4-Phenylbutanoyl chloride. To a mixture of 4-phenylbutanoic acid (12.0 g, 0.73 mol) in 60 ml of dichloromethane was added oxalyl chloride (12.8 ml, 0.15 mol). This was then stirred at room temperature until gas evolution ceased (2 hrs.). The reaction mixture was then evaporated to yield a yellow oil (13.1 g, 98.1%) which was used without further purification. IR (neat) 1799.6 cm C=O (acid chloride). C. N-Benzyloxycarbonyl-2-(S)-[N-(4-phenyl-l-keto-butane)-2-acetoxyethanamide oximef-pyrrolidine. N-benzyloxycarbonyl-2-(S)-(2-acetoxyethanamide oxime)-pyrrolidine hydrochloride (12.0 g, 0.032 mol) was dissolved in a mixture of toluene (60 ml) and chloroform (35 ml). This mixture was then cooled to 0°C and triethylamine (6.8 ml, 0.049 mol) was added. After 5 min. 4-phenylbutanoyl chloride (7.0 g, 0.038 mol) in chloroform (15 ml) was added dropwise. The reaction mixture was then allowed to warm to room temperature overnight. After this time the mixture was filtered and the solvent evaporated. This residue was then purified by column chromatography (silica gel; ethyl acetate:hexane, 30:70 to 70:30) to give the product (3.91 g, 25.2%) as a thick oil. MS 482 (M + 1). •HNMR (CDC1 3 ) δ 1.7 - 2.2 (m, 9H); 2.42 (t, 2H, J = 7.7 Hz); 2.69 (t, 2H, J = 7.7 Hz); 3.3 - 3.6 (m, 2H); 4.34 (m, 1H); 5.0 - 5.3 (m, 4H); 5.58 (b, 1H); 7.1 - 7.4 (m, 10H). D. N-Benzyloxycarbonyl-2-(S)-[acetoxy-(3-(3-phenylpropane)-l, 2, 4-oxadiazolyl)- methanej-pyrrolidine. In toluene ( 100 ml) was placed N-Benzyloxycarbonyl-2-(S)-[N-(4-phenyl- 1 -keto- butane)-2-acetoxyethanamide oxime]-pyrrolidine (3.91 g). This mixture was then refluxed for 90 hrs. After this time the reaction was evaporated and the residue purified by column chromatography (silica gel; ethyl acetate:hexane, 0:100 to 50:50) to give the product (2.86 g, 73.7%) as a pale yellow oil. MS 464 (M + 1). 'HNMR (CDC1 3 ) δ 1.7 - 2.3 (m, 9H); 2.39 (t, 2H, J = 7.4 Hz); 2.69 (t, 2H, J = 7.4 Hz); 3.4 - 3.7 (m, 2H); 4.0 - 4.7 (m, 1H); 5.0 - 5.3 (m, 2H); 5.7 - 6.4 (m, 1H). E. N-Benzyloxycarbonyl-2-(S)-[hydroxy-(3-(3-phenylpropane)-l,2,4-oxadiazolyl)- methanef-pyrrolidine. In methanol (100 ml) was placed N-Benzyloxycarbonyl-2-(S)-[acetoxy-(3-(3- phenylpropane)-l,2,4-oxadiazolyl)-methane]-pyrrolidine (2.86 g, 6.0 mmol). To this was added potassium carbonate (2.0 g, 14.5 mmol) in water (20 ml). This was then stirred at room temperature for 1 hr. At this time the reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (2 x 100 ml). The organic layer was dried (anhydrous magnesium sulfate) and the solvent evaporated to yield the product (2.36 g, 94.0%) as a pale yellow oil. This was then used without further purification. F. 2-(S)-[Hydroxy-(3-(3-phenylpropane)-l,2,4-oxadiazolyl)-methane]-pyrrolidine. N-Benzyloxycarbonyl-2-(S)-[hydroxy-(3-(3-phenylpropane)-l,2,4-oxadiazolyl)- methane]-pyrrolidine (2.36 g, 5.6 mmol) was dissolved in trifluoroacetic acid (50 ml). This was then cooled to 0°C and thioanisole (1.0 ml, 8.5 mmol) was added and the reaction allowed to warm to room temperature overnight. After this time the reaction mixture was evaporated and the residue taken up into ether. The ether was extracted with 2N hydrochloric acid and the aqueous layer was washed with ether. The aqueous layer was then neutralized with sodium bicarbonate and then extracted with ether. The organic layer was then dried (anhydrous magnesium sulfate) and evaporated to yield the product (0.46 g, 29.3%) as a yellow oil. This was then used without further purification. MS 288 (M + 1). Η NMR (CDC1 3 ) δ 1.5 - 2.2 (m, 9H); 2.6 - 2.7 (m, 2H); 2.8 - 2.9 (m)2H); 3.4 - 3.6 (m, 1H); 4.5 - 4.7 (m, 1H); [4.77 (d, J = 9.99), 5.03 (d, J = 1.8), 1H]; 5.88 (b, 1H); 7.1 - 7.4 (m, 5H). G. N-(4-phenyl-ketobutane)-(L)-proline t-butyl ester. To a solution of (L)-proline t-butyl ester hydrochloride (5.0 g, 0.024 mol) in toluene (50 ml) and chloroform (30 ml), at 0°C, was added triethylamine (5.0 ml, 0.036 mol). After 5 min., 4-phenylbutanoyl chloride (5.0 g, 0.027 mol) was added and the reaction allowed to warm to room temperature overnight. After this time the reaction mixture was filtered and the solvent evaporated. The residue was then purified by column chromatography (silica gel; ethyl acetate:hexane, 0:100 to 50:50) to yield the product (5.0 g, 65.4%) as a pale yellow oil. MS 318 (M + 1). Η NMR (CDC1 3 ) δ [1.42 (s), 1.46 (s), 9H]; 1.8 - 2.4 (m, 8H); 2.68 (t, 2H, J = 7.4); 3.3 - 3.7 (m, 2H); [4.17 (dd, J = 2.8, J = 8.5), 4.39 (dd, J = 3.6, J = 8.5), 1H]; 7.1 - 7.4 (m, 5H). H. N-(4-phenyl-ketobutane)-(L)-proline. To a solution of N-(4-phenyl-ketobutane)-(L)-proline t-butyl ester (5.0 g) in dichloromethane (50 ml), cooled to 0°C, was added trifluoroacetic acid (20 ml). After 3 hrs. the reaction mixture was concentrated and then taken up in ethyl acetate. This was then extracted with 2N sodium hydroxide solution. This aqueous solution was then washed with ethyl acetate before it was neutralized with 4N hydrochloric acid. Then the aqueous layer was extracted with ethyl acetate and the organic layer dried (anhydrous magnesium sulfate) and the solvent evaporated. This yielded the product (4.1 g, >95%) as a thick oil. MS 262 (M + 1). 'H NMR (CDC1 3 ) δ 1.8 - 2.3 (m, 4H); 2.38 (t, 2H, J = 7.1 Hz); 2.69 (t, 2H, J = 7.4 Hz); 3.3 - 3.6 (m, 2H); 4.57 (q, 1H, J = 4.0); 7.1 - 7.4 (m, 5H); 12.08 (s, 1H). I. N-[N-(4-Phenyl-l-ketobutane)-(L)-prolyl]-2-(S)-[hydroxy-(3-(3-phenylpropane)- 1, 2, 4-oxadiazolyl)-methane]-pyrrolidine. In dry dimethylformamide (20 ml) at 0°C, was placed N-(4-phenyl-ketobutane)-(L)- proline (0.46 g, 1.76 mmol) along with HOBT (0.30 g, 2.29 mmol) and EDCI (0.35, 1.94 mmol). This was then kept at 0°C for 30 min. After this time 2-(S)-[Hydroxy-(3-(3- phenylpropane)- 1 ,2,4-oxadiazolyl)-methane]-pyrrolidine (0.48 g, 1.94 mmol) along with N- methyl morpholine (0.28 ml, 2.64 mmol) were added dropwise. This mixture was then allowed to stir at 0°C overnight. At which time the mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, potassium hydrogen sulfate, and water. The organic layer was then dried (anhydrous magnesium sulfate) and the solvent evaporated. The remaining residue was purified by column chromatography (silica gel; ethyl acetate:hexane, 50:50) followed by RP-HPLC (acetonitrile: water, 40:60) to give the product (0.25 g, 26.8%) as a clear oil after lyophilization. MS 531 (M + 1). Η NMR (CDC1 3 ) δ 1.8 - 2.4 (m, 16H); 2.6 - 2.8 (m, 4H); 2.8 - 3.0 (m, 2H); 3.35 - 3.50 (m, 1H); 3.55 - 3.70 (m, 1H); 3.85 - 4.00 (m, 1H); 4.6 - 4.8 (m, 2H); 4.95 (d, 1H, J = 1.9 Hz); 7.1 - 7.4 (m, 1 OH). J. N-[N-(4-phenyl-l-ketobutane)-(L)-prolyl]-2-(S)-[(3-(3-phenylpropane)-l,2,4- oxadiazolyl)-ketomethane]-pyrrolidine. In dry toluene (10 ml) was placed N-chlorosuccinimide (0.25 g, 1.89 mmol) and this was cooled to 0°C. Then dimethylsulfide (0.20 ml, 2.69 mmol) was added and allowed to stir for 30 min. at 0°C. After this time the mixture was cooled to -25°C and N-[N-(4-Phenyl-l- ketobutane)-(L)-prolyl]-2-(S)-[hydroxy-(3-(3-phenylpropane)-l,2,4-oxadiazolyl)-methane]- pyrrolidine (0.25 g, 0.47 mmol) in dry toluene (20 ml) was added dropwise. After 1 hr. TEA (triethylamine)(0.19 gm, 1.89 mmol) was added and the mixture was allowed to warm to room temperature. The resulting mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was then dried (anhydrous magnesium sulfate) and the solvent evaporated. The residue was then purified by RP-HPLC (acetonitrile:water, 15:85 to 100:0) to yield the product (0.16 g, 64%) as a clear oil after lyophilization. MS 529 (M + 1). Η NMR (CDC1 3 ) δ 1.8 - 2.4 (m, 14H); 2.65 (t, 2H, J = 7.7 Hz); 2.72 (t, 2H, J = 7.4 Hz); 2.93 (t, 2H, J = 7.4 Hz); 3.32 - 3.46 (m, IH); 3.5 - 3.6 (m, IH); 3.66 - 3.76 (m, IH); 3.9 - 4.02 (m, IH); 4.66 - 4.74 (m IH); 5.46 (q, IH, J = 3.1 Hz, J = 5.5 Hz); 7.1 - 7.4 (m, 10H). ,3 CNMR (CDC1 3 ) δ 24.62, 25.33, 25.83, 25.96, 27.84, 28.40, 28.43, 33.57, 34.90, 35.25, 47.05, 47.12, 47.24, 57.45, 62.92, 75.40, 75.83, 76.26, 125.83, 126.32, 128.31, 128.50, 128.54, 128.58, 140.40, 141.80, 164.41, 170.70, 171.65, 181.10, 189.62. C 3 ,H 36 O 4 N 4 %C %H %N Theory 70.42 6.87 10.60 Found 69.97 6.73 10.12 Example II - Synthesis of Acetyl-L-leucyl-N-[l-[2-[(5-phenyl)-l,3,4-oxadiazolyl]carbonyl]- 4-(guanidino)-butyl]-L-leucyl]amide) (CQ-0002). 2-Phenyl-1, 3, 4-oxadiazole intermediate Benzoyl hydrazide (200 mg) freshly crystallized from chloroform was suspended in 5 mL of triethyl orthoformate and heated at reflux under nitrogen in a 160 °C oil bath for 3 hours. The mixture was cooled to room temperature, chilled in ice, and treated with 50 mL water and 10 mL 10% KHSO 4 solution. The mixture was stirred approximately 2 minutes then 50 mL of EtOAc was added and stirring continued for 10 minutes. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. All ethyl acetate layers were combined and were washed with 10% sodium bicarbonate solution and saturated sodium chloride solution. Drying over sodium sulfate, rotary evaporation and further drying under high vacuum provided 204 mg of an analytically pure oil which crystallizes upon standing. Commercially available benzoylhydrazide (Aldrich) in this reaction may be used, but the resulting product often contains a minor impurity which can be removed following the cyclization, by flash chromatography on silica gel eluting with 0 - 10% acetone in hexane. •H-NMR-CDCl j 7.49-7.62 (m, 3H), 8.12 (d, J=6, 2H), 8.49 (s, IH). A. Acetyl-L-leucyl-L-leucyl-arginine(Mtr) (N-methyl)-(N-Methoxy) -amide: Acetyl- Leu-Leu-OH (133 mg) and arginine (Mtr) -N-methyl-N-methoxy amide (200 mg) were dissolved in 10 mL of DMF and were treated with 243 uL of DIEA nd 212 mg of HBTU. The reaction stirred at room temperature for 15 hours and was worked up according to method A. Drying over Na^O^ rotary evaporation of the solvent and flash chromatography on silica gel (50% acetone in hexane) provided 270 mg of the title compound as a foam. B. Acetyl-L-leucyl-N-[l-[2-[(5-phenyl)-l,3,4-oxadiazolyl]carbonyl]-4-[(4-methoxy- 2, 3, 6-trimethyl-benzenesulphonyl)-guanidino] -butyl] -L-leucyl amide: 2-phenyl- 1 ,3,4- oxadiazole (194 mg) in 2 mL of dry THF was chilled to -78° C. n-Butyllithium (1.46 mmole) was added as a 2.5 M solution in hexanes. The reaction stirred 20 minutes at -78 °C and was then placed in a 0°C cooling bath. Acetyl-Leu-Leu-Arg-(Mtr)-N-(CH 3 )-OCH 3 was then added in 2 mL of dry THF. The reaction was placed in a room temperature water bath and stirred 1 hour, then the solution was chilled to 0°C, and 20 mL of saturated ammonium chloride solution was added under nitrogen with rapid stirring. After the several minutes of vigourous stirring the solution was extracted with EtOAc. The ethyl acetate solution was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to a pale brown oil by rotary evaporation. C. Acetyl-L-leucyl-N-[l-[2-[(5-phenyl)-l,3,4-oxadiazolyl]carbonyl]-4-(guanidino)- butyl] -L-leucyl amide: One half of the crude product from step B was dissolved in a preformed solution of 2 mL of TFA and 100 uL thioanisole. The reaction stirred under nitrogen for 4 hours. The solvent was removed in vacuo, and the product was precipitated with dry ether. The precipitate was taken up in methanol and concentrated in vacuo, the residue was triturated with dry ether, and dried in vacuo to provide 22 mg of the title compound as a colorless powder. Samples for biological testing were obtained by reverse phase C18 chromatography (5-80% CH 3 CN, 0.1% TFA, over 40 minutes). MS m/z (M+H) + 571 (CQ- 0002). Example III - Measurement of Inhibitory Activity against Trypsin For K, measurement, bovine pancreatic trypsin (Sigma) was prepared at a concentration of 0.2 mg/mL in 0.05 M acetate buffer (pH5.1) containing 0.1M NaCl, 10 mM CaCl 2 , 0.005% Triton X-100 (v/v). The working stock of CQ-0002 was prepared in 0.1M HEPES buffer at pH 7.5, containing 0.1M NaCl, lOmM CaCl 2 , 0.005% Triton X-100 (v/v), 10% DMSO (v/v). The reaction was started by mixing enzyme (2μg/mL final concentration), inhibitor and substrate (D/L B APNA, 2mM final concentration) simultaneously in the assay buffer (0.1M HEPES, 0.1M NaCl, lOmM CaCl 2 , 0.005% Triton X-100 (v/v), 5% DMSO (v/v), pH7.5). Release of nitroaniline was monitored spectrophotometrically at 410nm over a 10 min time span at room temperature. Steady-state velocities were measured at different inhibitor concentrations and the IC 50 value was calculated using ENZFIT (Elsevier). The K, constant was calculated as: K, = IC 50 [I + (S/K- ]. Results are presented in Table 1. Example IN - Measurement of Inhibitory Activity Against Proteinase 3 (PR-3) The assays are performed essentially as described in the literature (Hoidal, et al., Meth. in Enzymol, 244:61-67 (1994); Fruh, et al, Biol. Chem., 377:579-586 (1996)). However, human neutrophil proteinase 3 (Athens Research and Technology, Inc.) was unstable during the assay. To prevent inactivation due to adsorption or aggregation of the enzyme, proteinase 3 was diluted 1 :40 using 0.05 M acetate buffer, containing 0.1 M ΝaCl and 0.005% Triton-X 100, pH 5.1. Proteinase 3 was stable due to the presence of Triton X- 100 during 4-6 hours on ice without any loss of activity. 50 mM Boc-Ala-OPhΝO 2 in DMSO was used as a substrate, final concentration was 0.625 mM. Residual activity of the enzyme was determined after preincubation of the enzyme (6 μi) with different concentrations of inhibitors at 25 °C in 0.1 M HEPES buffer, containing 0.1 M NaCl, 10 mM CaCl 2 , 0.0005% Triton X-100 and 5% DMSO, pH 7.5. The release of nitrophenol was monitored at 410 nm. Results are presented in Table 1. Example V - Measurement of Inhibitory Activity against Human Tryptase Each compound was diluted in 0.12M NaCl and added to lmL of 0.2mM tosyl-Gly- Pro-Lys-p-nitroanilide in 40mM HEPES, pH 7.4, at room temperature. Enzymatic reactions were initiated by addition of 30ng of purified human lung-derived tryptase that had been stabilized with 150ng of Dextran sulfate. Initial velocities were monitored spectrophotometrically at 410nm over a 1.5 min time sp.an. Percent inhibition was calculated as: [(vo - Vi) / v 0 ] x lOO. Example VI - Measurement of Inhibitory Activity against Prolyl Oligopeptidase The enzyme prolyl oligopeptidase (flavobacterium) and the substrate Z-Gly-Pro- NHMec 9-NHMec: 7-(4-methylcoumarylamide) were obtained from Sigma (St. Louis, MO). The enzyme assay was performed as described elsewhere (Tadashi Yoshimoto et al., J. Biol. Chem., 255, 4786-4792, 1980), except that a Quanta Master QM1 (Photon Technologies International, South Brunswick, NJ) was used and S«K m . The inhibitor was preincubated for 20 min at room temperature with the enzyme before starting the reaction by adding substrate. Four inhibitor concentrations were used to estimate the IC 50 value which approximates the Kj constant directly (Cheng, et al., Biochemical Pharmacology, 22:3099- 3108). Example Nil - Measurement of Inhibitory Activity Against Bovine α-Chymotrypsin (α- chym), porcine pancreatic elastase (PPE) and human cathepsin-G (Cat-G). Buffers were prepared as follows: 0.1 M HEPES, 0.1M ΝaCl, lOnM CaCl 2 , 0.005% Triton X-100, pH7.5 (assay buffer); 0.05M ΝaCH 3 CO 2 , 0.1M NaCl, lOmM CaCl 2 , pH 5.1 (enzyme dilution buffer). The following substrates were used: N-succinyl-Ala-Ala-Pro-Leu-pNA (α-chym, PPE) was prepared as a 200mM stock in DMSO. N-succinyl-Ala-Ala-Pro-Phe-pNA (Cat-G) was prepared as a 100 mM stock in DMSO. The final substrate concentrations for the assays were 0.5mM, LOmM and 2.0mM for α-chym, Cat-G and PPE, respectively. The enzyme α-chym was in a 2.0 mg/ml stock solution. An aliquot was diluted to 0.025 mg/ml in the enzyme dilution buffer. PPE was a 2.0 mg/ml solution. The material was diluted to 0.05 mg/ml in dilution buffer. Cat-G (lmg) was prepared at a concentration of 2 mg/ml in dilution buffer as a stock. Aliquots of this were further diluted to 0.2 mg/ml. The following reagents were applied to 1-ml cuvettes (Dynalab): 0.945 ml assay buffer; (40-x) μl DMSO (final concentration of DMSO was 5%); x μl diluted inhibitor (from lOmM stocks); and 10 μl substrate. The reaction was commenced with the addition of enzyme (5μl). The formation of product p-nitroaniline was monitored at 410 nm in a spectrbphotometer over 15-30 min. Steady-state velocities were determined and processed using a software program (ENZFIT, Elsevier), generating the IC 50 values. From these data, the Kj values were determined using the equation: K, = I 50 /[l + ([Sj/KL,,,)]. Results are presented in Table 1. Table 1. 00 CO 00 m o CO o m = ?σ 10 po 15 00 <= CO 00 m o m - » 10 m σ. 15

Claims: We claim: 1. A method of inhibiting the enzymatic activity of a serine protease comprising contacting such protease with an inhibitory amount of a compound of formula (I): (I) wherein Z is a serine protease binding moiety; R, is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxy; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C 5 -C, 2 ) aryl, (C 5 -C 12 )arylalkyl or (C 5 -C, 2 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, alkylenedioxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; and Y and X are independently O, S or N, said N being optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C 5 -C 6 ) aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; wherein at least one of Y or X is N; or a pharmaceutically acceptable salt thereof. A method of claim 1 wherein Z is of the formula (II): R,. R 4 (II) wherein AA,, AA 2 , AA 3 , AA 4 and AA 5 are independently an amino acid residue or amino acid residue mimetic; a direct bond or absent; and R 4 and R 4 ' are independently -C(O)R 5 , -C(O)NHR 5 , -S(O) 2 R 5 , -C(O)OR 5 , -C(O)-(C 5 - C 6 )aryl-C(O)-R 5 , -CR 5 or R 5 , where R 5 is H, alkyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, hydroxy, alkoxy, haloalkyl, amino, aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy or alkylcarboxamide; cycloalkyl, alkylcycloalkyl, (C 5 -C, 2 ) aryl or (C 5 -C, 2 )arylalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, alkoxy, haloalkyl, amino, aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkyl, alkenyl, alkynyl or (C 5 -C 12 )aryl; or absent; or together R 4 and R 4 ' form a ring comprising 5-7 atoms selected from C, N, S and O. 3. A method of claim 2 wherein Z comprises a pentapeptidyl binding moiety. 4. A method of claim 2 wherein Z comprises a tetrapeptidyl binding moiety. 5. A method of claim 2 wherein Z comprises a tripeptidyl binding moiety. 6. A method of claim 2 wherein Z comprises a dipeptidyl binding moiety. 7. A method of claim 2 wherein the amino acids are selected from arginine or an arginine mimetic; proline; aspartic and glutamic acid and the aryl and alkyl esters thereof; alanine and glycine optionally substituted at the α-carbon or α-nitrogen with alkyl, cycloalkyl or aryl; leucine, isoleucine; cysteine optionally substituted at the sulfur atom with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo- phenylalanine, dehydro-phenylalanine, indoline-2-carboxylic acid; tetrahydroisioquinoline-2- carboxylic acid optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tyrosine, serine or threonine optionally substituted with alkyl or aryl; tryptophan, histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysine optionally substituted at the nitrogen atom with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or cycloalkyl, bicycloalkyl, cycloalkyl alkyl, bicycloalkyl alkyl or fused aryl-cycloalkyl alkyl optionally comprising 1 or more heteroatoms selected from N, O and S. 8. A method of claim 2 wherein AA, is an amino acid residue or amino acid residue mimetic, or of the formula (Ilia): (Hla) wherein X' is CR 2 ' or N; and R 2 , R 2 ' and R 2 " are independently H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxy, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or - RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C 5 -C 6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl- oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C 5 -C, 2 ) aryl, (C 5 -C, 2 )arylalkyl or (C 5 - C, 2 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with hydroxy, halo, cyano, keto, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; or R 2 and R 2 ' together with X' form a ring comprising 4-7 atoms selected from C, N, S and O, said ring optionally subsitituted with hydroxy, halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkyl amidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio. 9. A method of claim 8 wherein AA 2 is an amino acid residue, or of the formula (Illb): or selected from a mimetic of formulas IN to XXIN: wherein X" is CR' 3 or N; R 3 , R' 3 and R" 3 are independently H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxy, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or - RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C 5 -C 6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl- oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C 5 -C 12 ) aryl, (C 5 -C I2 )arylalkyl or (C 5 - Cι 2 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with hydroxy, halo, cyano, keto, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; m is 0, 1 or 2; n is 0, 1 or 2; G is -C(O)-, -NHC(O)-, -S(O) 2 -, -OC(O)-, -C- or a direct bond; ^, R 7 , R' 6 , R' 7 are independently H, alkyl, alkenyl, halo, alkoxy, carboxyl, carboalkoxy, amino, aminoalkyl, dialkylamino; cycloalkyl, (C 5 -C 6 ) aryl or (C 5 -C 6 ) arylalkyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, guanidine, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine; and U, V, W and Y' are independently or together N, C, C(O), N(R,) where R, is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, S and N, and optionally subsituted with halo or alkyl; N(R 10 ) where R, 0 is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fused aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, guanidine, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine; or C(R,,)(R, 2 ) where R,, and R, 2 are independently or together H, alkyl, alkythio, alkythioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally subsituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine. 10. A method of claim 9 wherein AA 3 , AA 4 and AA 5 are independently a direct bond or absent; or an amino acid selected from arginine or an arginine mimetic; proline; aspartic and glutamic acid and the aryl and alkyl esters thereof; alanine or glycine optionally substituted at the α-carbon or α-nitrogen with alkyl, cycloalkyl or aryl; leucine, isoleucine; cysteine optionally substituted at the sulfur atom with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydro-phenylalanine, indoline-2- carboxylic acid; tetrahydroisoquinoline-2-carboxylic acid optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tyrosine, serine or threonine optionally substituted with alkyl or aryl; tryptophan, histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, omithine and lysine optionally substituted at the nitrogen atom with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or cycloalkyl, bicycloalkyl, cycloalkyl alkyl, bicycloalkyl alkyl or fused aryl-cycloalkyl alkyl optionally comprising 1 or more heteroatoms selected from N, O and S; 11. A method of claim 8 wherein X' is N. 12. A method of claim 9 wherein X" is N. 13. A method of claim 8 wherein X' is CR' 2 , and R' 2 is H. 14. A method of claim 9 wherein X" is CR' 3 , and R' 3 is H. 15. A method of claim 9 wherein said protease is thrombin. 16. A method of claim 15 wherein AA, is Arg or an Arg mimetic. 17. A method of claim 15 wherein X' is CR' 2 and R 2 is alkyl or alkenyl substituted with guanidinyl, amino or amidylguanidine; benzyl optionally substituted with amidine; alkyl- or alkyl-amino pyridine; alkyl- or alkyl-aminoimidazole substituted with amino; or alkylcyclohexane optionally comprising nitrogen and optionally substituted with keto and amidine. 18. A method of claim 17 wherein R 2 is -CH 2 (CH 2 ) 2 NHC(=NH)NH 2 ; -CH 2 (CH 2 ) 4 NH 2 ; benzylamidine; -CH 2 (CH 2 ) 2 NH-pyridine; -CH 2 NHC(O)NHC(=NH)NH 2 ; -CH 2 CH 2 CH 2 - (imidazole)-NH 2 ;- or -CH 2 CH 2 NH-(imidazole)-NH 2 ; or -CH 2 -(N,N-diketocyclohexane)- C(=NH)NH 2 . 19. A method of claim 18 wherein AA 2 is Gly. 20. A method of claim 2 or 9 wherein said serine protease is plasmin. 21. A method of claim 20 wherein AA, is Arg or Arg mimetic; optionally substituted Lys or Orn. 22. A method of claim 21 wherein AA, is Lys. 23. The method of claim 21 where -AA 3 -AA 2 - is -Pro-Phe-. 24. A method of claim 2 or 9 wherein said serine protease is trypsin. 25. A method of claim 24 wherein AA, is Arg or Arg mimetic, or optionally substituted Lys. 26. A method of claim 2 or 9 wherein said serine protease is plasma kallikrein. 27. A method of claim 26 wherein Z is where AA, is Arg or Arg mimetic, or optionally substituted Lys. 28. A method of claim 27 wherein AA 2 is Phe, Met or Leu; and AA 3 is Pro. 29. A method of claim 2 or 9 wherein said serine protease is tissue kallikrein. 30. A method of claim 29 wherein Z is R 4 -AA 4 -AA 3 -AA 2 -AA,- where AA, is Arg or Arg mimetic. 31. A method of claim 30 wherein AA 2 is Leu or Phe; and AA 3 is Arg or Arg mimetic, or Pro. 32. A method of claim 31 wherein AA 4 is Thr 33. A method of claim 2 or 9 wherein said serine protease is a guanidinobenzoatase. 34. A method of claim 33 wherein AA, is Arg, Arg mimetic or guanidinobenzoyl. 35. A method of claim 2 or 9 wherein said serine protease is chymase. 36. A method of claim 35 wherein Z is R 4 -AA 5 -AA 4 -AA 3 -AA 2 -AA r where AA, is Tyr, Phe, Trp or Leu. 37. A method of claim 36 wherein AA 2 is Pro. 38. A method of claim 37 wherein AA, is His. 39. A method of claim 38 wherein AA 4 is He; and AA 5 is Tyr. 40. A method of claim 36 wherein AA 2 is a mimetic of formulas IN to XXIV. 41. A method of claim 2 or 9 wherein said serine protease is mast cell tryptase. 42. A method of claim 41 wherein Z is R 4 -AA 3 -AA 2 -AA,- where AA, is Arg or Arg mimetic. 43. A method of claim 42 wherein AA 2 is Gly, Nal, Arg, Arg mimetic, Leu or Phe; and AA 3 is Leu, Arg, Arg mimetic, optionally substituted Lys or Ser, or Phe. 44. A method of claim 2 or 9 wherein said serine protease is prolyl oligopeptidase. 45. A method of claim 44 wherein AA, is Pro. 46. A method of claim 45 wherein AA 2 is Pro. 47. A method of claim 45 wherein the compound is Ν-[Ν-(4-phenyl-l-ketobutane)-(L)- prolyl] -2-(S)-[(3 -(3 -phenylpropane)- 1 ,2 ,4-oxadiazolyl)-ketomethane] -pyrrolidine. 48. A method of claim 2 or 9 wherein said serine protease is hepatitis C virus NS3 polyprotein endopeptidase. 49. A method of claim 48 wherein Z is where AA, is Cys. 50. A method of claim 49 wherein AA 2 is Cys or Ala. 51. A method of claim 50 wherein AA 3 is Nal. 52. A method of claim 51 wherein AA 4 is Nal. 53. A method of claim 2 or 9 wherein said serine protease is human cytomegalovirus protease. 54. A method of claim 53 wherein Z is x 4~ V-A.4~ AA3 ~I J . -AA J " where AA, is Ala. 55. A method of claim 54 wherein AA 2 is optionally substituted Asn or Gin; Asp or Glu or an ester thereof, or optionally substituted Lys; AA 3 is Nal, He or Leu; 56. A method of claim 55 wherein AA 4 is Nal, a direct bond or absent. 57. A method of claim 2 or 9 wherein said serine protease is an assemblin. 58. A method of claim 57 wherein Z is where AA, is Ala. 59. A method of claim 58 wherein AA 3 is Leu, Nal or He; 60. A method of claim 59 wherein AA 4 is optionally substituted Tyr, a direct bond or absent. 61. A method of claim 60 wherein AA 2 is optionally substituted Gin or Lys. 62. A method of claim 2 or 9 wherein said serine protease is u-plasminogen activator. 63. A method of claim 62 wherein Z is -K4~ A_A4~.AA.3~ AA.2~ AA j ~ where AA, is Arg, Arg mimetic or optionally substituted Lys. 64. A method of claim 63 wherein AA 2 is Gly; and AA 3 is optionally substituted Ser. 65. A method of claim 64 wherein AA 4 is Gly. 66. A method of claim 2 or 9 wherein said serine protease is t-plasminogen activator. 67. A method of 66 wherein Z is where AA, Arg, Arg mimetic or optionally substituted Lys. 68. A method of claim 67 wherein AA 2 is Gly or Ala; and AA 3 is Arg or Arg mimetic. 69. A method of claim 1 wherein said serine protease is Schistosoma serine protease. 70. A method of claim 2 or 9 wherein AA, is Arg, Arg mimetic, or optionally substituted Lys or Orn. 71. A method of claim 70 wherein AA 2 is Phe. 72. A method of claim 71 wherein AA 3 is Pro. 73. The method of claim 1 wherein said method is effective to inhibit microbial growth. 74. The method of claim 1 or 72 wherein said method is effective to reduce perioperative blood loss. 75. The method of claim 1 or 72 wherein said method is effective to preserve transplantation tissues or organs. 76. The method of claim 1 wherein said method is effective to inhibit cancer cell growth or tumor progression or tumor metastasis or invasion. 77. The method of claim 1 wherein said method is effective to treat the symptoms associated with pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis. 78. The method of claim 1 wherein said method is effective to treat the symptoms associated with bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy. 79. The method of claim 1 or 2 wherein said method is effective to treat the symptoms associated with atherosclerosis or reperfusion injury. 80. The method of claim 1 or 44 wherein said method is effective to treat the symptoms associated with Alzheimer's disease. 81. The method of claim 1 or 35 whererin said method is effective to treat the symptoms associated with hypoxia or ischemia. 82. The method of claim 1 wherein said method is effective to treat the symptoms associated with blood coagulation disorders. 83. A method of detecting or quantifying the activity of a serine protease in a pure sample, mixture or a biological fluid or tissue, comprising contacting said protease with a compound of formula (I): (I) wherein Z is a serine protease binding moiety; R, is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxy; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C 5 -C, 2 ) aryl, (C 5 -C 12 )arylalkyl or (C 5 -C I2 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, alkylenedioxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; and Y and X are independently O, S or N, said N being optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C 5 -C 6 ) aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; wherein at least one of Y or X is N; or a pharmaceutically acceptable salt thereof. 84. A method of purifying a serine protease in a sample, comprising contacting said protease with a compound of formula (I): (I) wherein Z is a serine protease binding moiety; R, is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxy; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C 5 -C 12 ) aryl, (C 5 -C, 2 )arylalkyl or (C 5 -C, 2 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, alkylenedioxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; and Y and X are independently O, S or N, said N being optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C 5 -C 6 ) aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; wherein at least one of Y or X is N; or a pharmaceutically acceptable salt thereof. 85. N-[N-(4-phenyl-l-ketobutane)-(L)-prolyl]-2-(S)-[(3-(3-phenylproρane)-l,2,4- oxadiazolyl)-ketomethane]-pyrrolidine. 86. N-(Benzyloxycarbonyl)-L-valyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-N-benzylglycinamide; N-Succinyl-L-valyl-N-[ 1 -[3-[5-(3-trifluoromethylbenzyl)- 1 ,2,4- oxadiazolyl] carbonyl] -2-phenylethylenyl] -L-prolinamide; N-[4-(4-Mo holinylcarbonyl)benzoyl]-L-valyl-N-[ 1 -[3-[5-(3- trifluoromethylbenzyl)-l,2,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L- prolinamide; and N-Acetyl-L-alanyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide. 87. N-(Benzyloxycarbonyl)-L-valyl-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]- 1 -methylethyl]-L-prolinamide; N-(Benzyloxycarbonyl)-L-t-butylglycyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)- l,2,4-oxadiazolyl]carbonyl]-2-methylpropyl]-L-prolinamide; N-(Benzyloxycarbonyl)-L-Nalyl-N-[l-[3-[5-(naphthyl-2-methylene)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide; N-(Benzyloxycarbonyl)-L-TIC-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-Methylpropyl]-L-Prolinamide; N-(3-Pyridylcarbonyl)-L-Valyl-N-[ 1 -[3-[5-(3-methylbenzyl)-l ,3,4- oxadiazolyl]carbonyl]-2-(S)-Methylpropyl]-L-Prolinamide; and N-(Methanesulfonyl)-L-valyl-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide. 88. N-(Phenylsulfonyl)-L-valyl-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide; N-(3-Pyridylcarbonyl)-L-valyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)-l,2,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide; N-(4-Pyridylmethyleneoxycarbonyl)-L-valyl-N-[l-[3-[5-(3-trifluoromethylbenzyl)- l,2,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide; N-(4-Pyridylmethyleneoxycarbonyl)-L-valyl-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide; and N-(Pyrrolyl-2-carbonyl)-L-valyl-N-[l-[2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-N-(l-indanyl)glycinamide.

Inventors: CHERONIS JOHN C, GYORKOS ALBERT C, LEIMER AXEL H, SPRUCE LYLE W, CHERONIS, JOHN, C., GYORKOS, ALBERT, C., LEIMER, AXEL, H., SPRUCE, LYLE, W.
Applicants: CHERONIS JOHN C, CORTECH INC, GYORKOS ALBERT C, LEIMER AXEL H, SPRUCE LYLE W, CHERONIS, JOHN, C., CORTECH, INC., GYORKOS, ALBERT, C., LEIMER, AXEL, H., SPRUCE, LYLE, W.
Application year: 1998
Main classification: C07K5
IPC codes: A61K38, A61P7, A61P9, A61P11, A61P25, A61P31, A61P35, C07K5, C12N9, C12Q1