Cysteine protease inhibitors

• US 6,004,933 A
• Filed: 04/23/1998
• Issued: 12/21/1999
• Est. Priority Date: 04/25/1997
• Status: Expired due to Fees

• Current Assignee: Cortech, Inc. (Kent International Holdings, Inc.)
• Original Assignee: Cortech, Inc. (Kent International Holdings, Inc.)
• Inventors: Leimer, Axel H., Gerrity, James Ivan, Goodfellow, Val S., Cheronis, John C., Spruce, Lyle W., Young, John M., Gyorkos, Albert C.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Solola, Taofiq A.
• Application Number:
  US09/065,258
• Time in Patent Office: 607 Days
• Field of Search: 548/125, 548/484, 548/17, 514/17, 514/18, 514/19, 514/213, 514/249, 514/259, 514/299, 514/387, 540/523, 544/182, 544/237, 544/240, 544/298, 544/354, 544/358, 546/164
• US Class Current: 514/3.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 5/06043 Leu-amino acid
• CPC Class Codes: C07K 5/06052 Val-amino acid
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0819 with the first amino acid being acidic
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to cysteine protease inhibitors of the general formula (I): ##STR1## wherein Z is a cysteine protease binding moiety; X and Y are S, O or optionally substituted N; and R₁ is optionally substituted alkyl or aryl.

Claims

1. A cysteine protease inhibitor of formula (I):

##STR12## wherein Z is a peptide or peptide mimetic cysteine protease binding moiety having between 2 and 5 amino acid residues or amino acid mimetics for between 1 and 5 amino acid residues, wherein the sum of the amino acid residues and the amino acid residues for which there is one or more amino acid mimetics is between 2 and 5 and the cysteine protease binding moiety is capable of binding to a cysteine protease;

R₁ is alkyl or alkenyl, optionally substituted with 1-3 halo or hydroxy, alkylamino, dialkylamino, alkyldialkylamino, or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂) aryl;

(C₅ -C₁₂)arylalkyl or(C₅ -C₁₂)arylalkenyl, wherein the aryl groups of the arylalky or arylalkenyl comprises 0-4 heteroatoms selected from N, O and S, and are optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide, alkylthio or haloalkylthio; and

one of Y and X is O and the other is N, said N being optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms;

(C₅ -C₆) aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, 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.

2. An inhibitor of claim 1 wherein Z is of the formula (II):

##STR13## wherein AA₁, AA₂, AA₃, AA₄ and AA₅ are independently an amino acid residue or amino acid residue mimetic;

a direct bond or absent; and

R₄ and R₄ '"'"' are independently --C(O)R₅, --C(O)NHR₅, --S(O)₂ R₅, --C(O)OR₅, --CR₅ or R₅, where R₅ is H, alkyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy or alkylcarboxamide;

cycloalkyl, alkylcycloalkyl, (C₅ -C₁₂) aryl or (C₅ -C₁₂)arylalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkyl, alkenyl, alkynyl or (C₅ -C₁₂)aryl;

or absent;

or together R₄ and R₄ '"'"' form a ring comprising 5-7 atoms selected from C, N, S and O.

3. An inhibitor of claim 2 wherein the cysteine protease binding moiety comprises (i) amino acids, (ii) amino acids and amino acid mimetics, or (iii) amino acid mimetics, wherein the moiety corresponds to a peptide of 5 amino acid residues.

4. An inhibitor of claim 2 wherein the cysteine protease binding moiety comprises (i) amino acids, (ii) amino acids and amino acid mimetics, or (iii) amino acid mimetics, wherein the moiety corresponds to a peptide of 4 amino acid residues.

5. An inhibitor of claim 2 wherein the cysteine protease binding moiety comprises a (i) amino acids, (ii) amino acids and amino acid mimetics, or (iii) amino acid mimetics wherein the moiety corresponds to a peptide of 3 amino acid residues.

6. An inhibitor of claim 2 wherein the cysteine protease binding moiety comprises a (i) amino acids, (ii) amino acids and amino acid mimetics, or (iii) amino acid mimetics wherein the moiety corresponds to a peptide of 2 amino acid residues.

7. An inhibitor of claim 2 wherein the amino acids are selected from argim ine 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 alkl, 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, dialkylarino, 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 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. An inhibitor of claim 2 wherein AA₁ is of the formula (IIIa):

##STR14## wherein X'"'"' is CR₂ '"'"' or N; and

R₂, R₂ '"'"' and R₂ " are independently H;

alkyl or alkenyl optionally substituted with 1-3 halo, hydroxy, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl;

--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 (C₅ -C₆)aryl;

or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, (C₅ -C12) aryl, (C₅ -C₁₂)arylalkyl or (C₅ -C₁₂)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with hydroxy, halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide, alkylthio or haloalkylthio;

or

R₂ and R₂ '"'"' 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, allyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide, alkylthio or haloalkylthio.

9. An inhibitor of claim 8 wherein AA₂ is of the formula (IlIb):

##STR15## or selected from a compound of formulas IV to XXV;

##STR16## wherein X" is CR'"'"'₃ or N;

R₃, 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;

--RCOR'"'"', --RCOOR'"'"' or --RC(O)NR'"'"'R" where R is alkyl or alkenyl, and R'"'"' and R" are independently H, alkyl, alkenyl, cycloalkyl or (C₅ -C₆)aryl;

or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, (C₅ -C₁₂) aryl, (C₅ -C₁₂)arylalkyl or (C₅ -C₁₂)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with hydroxy, halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)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;

R₆, R₇, R'"'"'₆, R'"'"'₇ are independently H, alkyl, alkenyl, halo, alkoxy, carboxyl, carboalkoxy, amino, aminoalkyl, dialkylamino;

cycloalkyl, (C₅ -C₆) aryl or (C₅ -C₆) arylalkyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alllylthio, guanidine, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine; and

U, V, W and Y'"'"' are independently or together N, C, C(O), N(R₉) where R₉ 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(R₁₀) where R₁₀ 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, haloalkoxy, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, guanidine, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine;

or C(R₁₁)(R₁₂) where R₁₁ and R₁₂ 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. An inhibitor of claim 9 wherein AA₃, AA₄ and AA₅ are 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;

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 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. An inhibitor of claim 8 wherein X'"'"' is N.

12. An inhibitor of claim 9 wherein X" is N.

13. An inhibitor of claim 8 wherein X'"'"' is CR'"'"'₂, and R'"'"'₂ is H.

14. An inhibitor of claim 9 wherein X" is CR'"'"'₃, and R'"'"'₃ is H.

15. An inhibitor of claim 10 wherein Z is a calpain binding moiety.

16. An inhibitor of claim 15 wherein R₂ is CH₃ SCH₂ CH₂ --, HOOC(CH₂)₂ CH₂ --, cyclohexyl-CH₂ --, imidazolyl-CH₂, (CH₃)₂ CHCH₂ --, (CH₃)₂ CH--, CH₃ CH₂ CH₂ -- or CH₃ (CH₂)₂ CH₂ --;

benzyl optionally substituted with alkoxy, OH or --O-benzyl;

H₂ NC(=⁺ NH₂)NHCH₂ CH₂ CH₂ --;

--R'"'"'--C(=⁺ NH₂)NH₂ ;

--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 alkyl; and

R" and R°

are alkyl or cycloalkyl.

17. An inhibitor of claim 16 wherein R₃ is --CH₂ -benzyl, benzyl, (CH₃)₃ C--, (CH₃)₃ CCH₂ --, (CH₃)₂ CH--, CH₃ (CH₂)₂ CH₂ --, CH₃ CH₂ CH(CH₃)-- or (CH₃)₂ CHCH₂ --.

18. An inhibitor of claim 17 wherein R₅ is benzyl, isoquinolinyl, quinolinyl, naphthyl or HOOCCH₂ C(CH₂ CH(CH₃)₂)--.

19. An inhibitor of claim 17 wherein R₄ is Cbz wherein the phenyl is optionally substituted with nitro.

20. An inhibitor of claim 17 wherein R₄ is toluenesulfonyl, methanesulfonyl, FMOC or (+)-menthyloxy-CO--.

21. An inhibitor of claim 16 wherein AA₃ is leucine, AA₄ and AA₅ are direct bonds or absent, and R₅ is alkyl.

22. An inhibitor of claim 7 wherein Z is

R₄ --Leu--Leu--Leu--;

R₄ --Leu--Leu--;

R₄ --Leu--Leu--Phe--;

R₄ --Leu--Abu--;

R₄ --Val--Phe--;

R₄ --Leu--Leu--Nle--;

R₄ --Ala--t--BuGly--Val--;

R₄ --t--BuGly--Val--;

R₄ --Leu--Leu--Met--;

or

R₄ --Leu--Nle--.

23. An inhibitor of claim 7 wherein Z is Cbz--Leu--Nle--;

or Cbz--Leu--Val--.

24. An inhibitor of claim 10 wherein Z is a cysteine cathepsin binding moiety.

25. An inhibitor of claim 24 wherein R₂ is CH₃ --, (CH₃)₂ CH--, (CH₃)₂ CHCH₂ --, CH₃ (CH₂)₂ CH₂ --, CH₃ CH(--O-benzyl)-- or benzyl--S--CH₂ --;

benzyl or --CH₂ -benzyl optionally substituted with OH or --OR'"'"' where R'"'"' is alkyl or aryl;

H₂ NC(=⁺ NH₂)NHCH₂ CH₂ CH₂ --;

--R'"'"'--C(=⁺ NH₂)NH₂ ;

--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 alkyl; and

R" and R°

are alkyl or cycloalkyl.

26. An inhibitor of claim 25 wherein R₃ is H, (CH₃)₂ CH--, (CH₃)₂ CHCH₂ --, CH₃ (CH₂)₂ CH₂ --, benzyl optionally substituted with hydroxy and halo;

(naphthyl)--CH₂ --;

H₂ N(CH₂)₃ CH₂ --, H₂ N(CH₂)₂ CH₂ --, H₂ NC(=⁺ NH₂)NHCH₂ CH₂ CH₂ --;

--R'"'"'--C(=⁺ NH₂)NH₂ ;

--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 alkyl; and

R" and R°

are alkyl or cycloalkyl.

27. An inhibitor of claim 24 wherein Z is a cathepsin B binding moiety.

28. An inhibitor of claim 27 wherein R₂ and R₃ are independently benzyl, --CH₂ -benzyl, H₂ N(CH₂)₃ CH₂ --, H₂ N(CH₂)₂ CH₂ --, H₂ NC(=⁺ NH₂)NHCH₂ CH₂ CH₂ --;

--R'"'"'--C(=⁺ NH₂)NH₂ ;

--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 alkyl; and

R" and R°

are alkyl or cycloalkyl.

29. An inhibitor of claim 27 or 28 wherein AA₃ is Ile or Leu.

30. An inhibitor of claim 28 wherein --AA₂ --AA₁ -- are

--Phe--hPhe--;

--Arg--hPhe--;

--Arg mimetic--hPhe--;

--Lys--hPhe--;

or

--Orn--hPhe.

31. An inhibitor of claim 24 wherein Z is a cathepsin L, O, K, or H binding moiety.

32. An inhibitor of claim 31 wherein Z is a cathepsin L binding moiety.

33. An inhibitor of claim 32 wherein R₃ is benzyl or (CH₃)₂ CHCH₂ --.

34. An inhibitor of claim 32 or 33 wherein R₂ is --CH₂ -benzyl.

35. An inhibitor of claim 24 wherein Z is a cathepsin S binding moiety.

36. An inhibitor of claim 35 wherein R₂ and R₃ are alkyl.

37. An inhibitor of claim 36 wherein R₂ and R₃ are independently (CH₃)₂ CH--, (CH₃)₂ CHCH₂ -- or CH₃ (CH₂)₂ CH₂ --.

38. An inhibitor of claim 35 wherein R₃ is benzyl, (CH₃)₂ CHCH₂ -- or (CH₃)₂ CH--.

39. An inhibitor of claim 35 or 38 wherein R₂ is --CH₂ -benzyl.

40. An inhibitor of claim 39 wherein AA₃, AA₄ and AA₅ are direct bonds or absent.

41. An inhibitor of claim 40 wherein R₅ is benzyl, isoquinolinyl, quinolinyl, naphthyl or HOOCCH₂ C(CH₂ CH(CH₃)₂)--.

42. An inhibitor of claim 41 wherein R is Cbz.

43. An inhibitor of claim 31 wherein Z is a cathepsin H binding moiety.

44. An inhibitor of claim 43 wherein Z is

R₄ --hPhe--;

or

HCl•

hPhe--.

45. An inhibitor of claim 31 wherein Z is a cathepsin K binding moiety.

46. An inhibitor of claim 45 wherein R₃ is benzyl, (CH₃)₂ CHCH₂ -- or (CH₃)₂ CH--.

47. An inhibitor of claim 45 or 46 wherein AA₃ is Gly;

and AA₄ is Val or D--Val.

48. An inhibitor of claim 7 wherein Z is a cathepsin K binding moiety;

and

AA₁ is Arg, Arg mimetic or hPhe;

AA₂ is Pro;

AA₃ is Gly; and

AA₄ is Val or D--Val.

49. An inhibitor of claim 7 wherein Z is a cathepsin K binding moiety;

and is

R₄ --Pro--AA₁ --;

R₄ --Gly--Pro--AA₁ --;

R₄ --Val--Gly--Pro--AA₁ ;

D--Val--Gly--Pro--AA₁ --;

or

R₄ --D--Val--Gly--Pro--AA₁ ;

where

AA₁ is Apa, Arg or Arg mimetic, or hphe.

50. An inhibitor of claim 24 wherein Z is

R₄ --AA₃ --Leu--hPhe--;

R₄ --AA₃ --Phe--hPhe--;

or

R₄ --AA₃ --Val--hPhe--;

where AA₃ is Gly, Val, D--Val, a direct bond or absent.

51. An inhibitor of claim 24 wherein Z is Mu--Val--hPhe--.

52. An inhibitor of claim 10 wherein Z is a caspase binding moiety.

53. An inhibitor of claim 52 wherein R₂ is --RCOOR'"'"'.

54. An inhibitor of claim 53 wherein R is --CH₂ -- and R'"'"' is H.

55. An inhibitor of claim 53 wherein AA₃ and AA₄ are amino acid residues and AA₅ is a direct bond.

56. An inhibitor of claim 55 wherein Z is an interleukin-1β

converting enzyme binding moiety.

57. An inhibitor of claim 56 wherein AA₄ is optionally substituted tyrosine or leucine.

58. An inhibitor of claim 57 wherein AA₃ is valine, glutamate or an ester thereof.

59. An inhibitor of claim 58 wherein R₃ is --CH₃ or (CH₃)₂ CH--.

60. An inhibitor of claim 56 wherein R₃ is --CH₃ or imidazolyl--CH₂ --;

AA₃ is valine or glutamate; and

R₅ is

--CH₃.

61. An inhibitor of claim 7 wherein Z is an interleukin-1β

converting enzyme binding moiety, and is

R₄ --AA₅ --AA₄ --AA₃ --Pro--AA₁ ;

where AA₁ is Asp or Asp ester.

62. An inhibitor of claim 61 wherein --AA₅ --AA₄ --AA₃ -- is

--Ala--;

--Glu--;

--Val--;

--Tyr--Ala--;

--Tyr--Glu--;

--Tyr--Val--;

--Leu--Ala--;

--Leu--Glu--;

or

--Leu--Val--.

63. An inhibitor of claim 10 wherein Z is an interleukin-1β

converting enzyme binding moiety and AA₂ is of the formula (VI);

wherein X" is CR'"'"'₃ ;

R₂ is --RCOOR'"'"' where R is alkyl or alkenyl, and R'"'"' is H, alkyl, alkenyl, cycloalkyl or (C₅ -C₆) aryl.

64. An inhibitor of claim 63 wherein R₃ and R'"'"'₃ are H.

65. An inhibitor of claim 63 wherein AA₃, AA₄ and AA₅ are direct bonds or absent, and R₂ is --RCOOH where R is --CH₂ --.

66. An inhibitor of claim 65 wherein R₆ is phenyl or benzyl substituted with halo.

67. An inhibitor of claim 66 wherein R₅ is benzyl, isoquinolinyl, quinolinyl, naphthyl or HOOCCH₂ C(CH₂ CH(CH₃)₂)--.

68. An inhibitor of claim 53 wherein Z is a YAMA binding moiety, where R is --CH₂ -- and AA₄ is Asp or an ester thereof.

69. An inhibitor of claim 68 wherein AA₃ is optionally substituted glutamine, or glutamic acid or an ester thereof.

70. An inhibitor of claim 69 wherein R₂ is (CH₃)₂ CH-- or CH₃ SCH₂ CH₂ --.

71. An inhibitor of claim 53 wherein Z is a FLICE binding moiety, where R₂ is --CH₂ -- and AA₄ is optinally substituted lysine.

72. An inhibitor of claim 71 wherein AA₃ is glutamic acid.

73. An inhibitor of claim 72 wherein R₃ is (CH₃)₂ CH--.

74. An inhibitor of claim 10 wherein Z is a viral or microbial cysteine protease binding moiety.

75. An inhibitor of claim 74 wherein Z is a gingipain binding moiety.

76. An inhibitor of claim 75 wherein Z is a gingipain K binding moiety.

77. An inhibitor of claim 76 wherein R₂ is RNR'"'"'R"R°

where R'"'"' is H;

R" and R°

are H or alkyl.

78. An inhibitor of claim 75 wherein Z is a gingipain R binding moiety.

79. An inhibitor of claim 78 wherein R₂ is H₂ NC(=⁺ NH₂)NHCH₂ CH₂ CH₂ --;

--R'"'"'--C(=⁺ NH₂)NH₂ ;

--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 alkyl; and

R" and R°

are alkyl or cycloalkyl.

80. An inhibitor of claim 7 wherein Z is a gingipain binding moiety, and AA₂ is proline.

81. An inhibitor of claim 80 wherein Z is R₄ --Leu--Pro--AA₁ --, where AA₁ is arginine or an arginine mimetic.

82. An inhibitor of claim 74 wherein Z is a human coronavirus protease binding moiety, and R₂ is

H₂ NC(=⁺ NH₂)NHCH₂ CH₂ CH₂ --;

--R'"'"'--C(=⁺ NH₂)NH₂ ;

--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 alkyl; and

R" and R°

are alkyl or cycloalkyl.

83. An inhibitor of claim 82 wherein R₃ is (CH₃)₂ CH--, (CH₃)₂ CHCH₂ -- or CH₃ (CH₂)₂ CH₂ --;

AA₃ is Asp or an ester thereof;

Leu, Arg or Arg mimetic, or direct bond;

AA₄ and AA₅ are direct bonds or absent; and

R₅ is alkyl.

84. An inhibitor of claim 74 wherein Z is a hepatitis A virus 3C proteinase binding moiety, and

R₂ is --RC(O)NR'"'"'R" where R'"'"' and R" are H or --CH₃ ;

or RCOOR'"'"' where R'"'"' is CH₃ ; and

AA₃ and AA₄ are amino acid residues.

85. An inhibitor of claim 84 wherein AA₄ is Leu.

86. An inhibitor of claim 85 wherein R₃ is --CH₃ and AA₃ is Ala.

87. An inhibitor of claim 7 wherein Z is a hepatitis A virus 3C proteinase binding moiety, and is

R₄ --Leu--AA₃ --Thr--Gln--;

R₄ --Trp--AA₃ --Thr--Gln--;

R₄ --Val--AA₃ --Thr--Gln--;

R₄ --Ile--AA₃ --Thr--Gln--;

or

R₄ --D--Leu--AA₃ --Thr--Gln--;

where AA₃ is Arg or Arg mimetic.

88. An inhibitor of claim 74 wherein Z is an Ad2 23K protease binding moiety, and

R₂ and R₃ are H;

AA₃ is alanine;

AA₄ is leucine;

AA₅ is a direct bond; and

R₄ is absent.

89. An inhibitor of claim 74 wherein Z is a human rhinovirus 3C protease binding moiety, and

R₂ is RCOOR'"'"' where R is --CH₂ --;

R₃ is benzyl; and

AA₃ is leucine or a direct bond.

90. An inhibitor of claim 74 wherein Z is a human rhinovirus 3C protease binding moiety, and R₂ is --RC(O)NR'"'"'R" where R'"'"' and R" are H or --CH₃ ;

or RCOOR'"'"' where R'"'"' is --CH₃ or --CH₂ CH₃ ;

or X'"'"' is N and R₂ is --CH₃.

91. An inhibitor of claim 74 wherein Z is human picomain 2A protease.

92. An inhibitor of claim 81 wherein R₃ is --CH(OR'"'"')CH₃ where R'"'"' is H, alkyl or aryl.

93. An inhibitor of claim 92 wherein R₂ is a hydrophobic side chain.

94. An inhibitor of claim 7 wherein Z is a human picomain 2A protease binding moiety, and is

R₄ --Ala--Ala--Pro--Val--;

or

R₄ --Ala--Ala--Pro--Ala--.

95. An inhibitor of claim 10 wherein Z is a protozoan protease binding moiety.

96. An inhibitor of claim 95 wherein Z is a Trypanosoma, Schistosoma or Leishmania protease binding moiety.

97. An inhibitor of claim 96 wherein R₂ is benzyl optionally subsituted with OH;

H₂ NC(=⁺ NH₂)NHCH₂ CH₂ CH₂ --;

--R'"'"'--C(=⁺ NH₂)NH₂ ;

--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 alkyl; and

R" and R°

are alkyl or cycloalkyl.

98. An inhibitor of claim 97 wherein R₃ is benzyl, (CH₃)₂ CHCH₂ -- or (CH₃)₂ CH--;

and AA₃ is Phe, Leu, Pro or a direct bond.

99. An inhibitor of claim 98 wherein R₄ is Boc or Suc.

100. An inhibitor of claim 95 wherein Z is a Plasmodium protease binding moiety.

101. An inhibitor of claim 100 wherein R₂ is (CH₃)₂ CH--;

--CH₂ -benzyl, benzyl or phenyl optionally substituted with hydroxyl;

alkylimidazoyl;

H₂ NC(=⁺ NH₂)NHCH₂ CH₂ CH₂ --;

--R'"'"'--C(=⁺ NH₂)NH₂ ;

--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 alkyl; and

R" and R°

are alkyl or cycloalkyl.

102. An inhibitor of claim 101 wherein R₃ is benzyl, (CH₃)₂ CHCH₂ --, (CH₃)₂ CH--, HOCH₂ -- or --CH₂ OR'"'"'.

103. An inhibitor of claim 100 wherein Z is

R₄ --Phe--Arg--;

R₄ --Phe--(arginine mimetic)--;

R₄ --Val--Leu--(arginine mimetic)--;

R₄ --Phe--Lys--;

R₄ --Leu--hPhe--;

R₄ --Val--Leu--Arg--;

R₄ --Phe(e--Z)--Lys--;

R₄ --Phe--Val--;

or

R₄ --Phe--Ser(OBzl)--.

104. An inhibitor of claim 100 wherein Z is

R₄ --Phe--AA₁ --;

or

R₄ --Leu--AA₁ --;

wherein AA₁ is optionally substituted lysine.

105. An inhibitor of claim 104 wherein R₄ is morpholino.

106. An inhibitor of claim 104 wherein R₄ is Cbz.

107. A method of inhibiting the enzymatic activity of one or more cysteine proteases comprising contacting a protease with an inhibitory amount of a compound of claim 1.

108. A method of inhibiting the enzymatic activity of one or more cysteine proteases comprising contacting a protease with an inhibitory amount of a compound of claim 10.

109. A method of inhibiting the enzymatic activity of a calpain cysteine protease comprising contacting a protease with an inhibitory amount of a compound of claim 15.

110. A method of inhibiting the enzymatic activity of a cysteine cathepsin comprising contacting the protease with an inhibitory amount of a compound of claim 24.

111. A method of inhibiting the enzymatic activity of a caspase comprising contacting the protease with an inhibitory amount of a comp ound of claim 52.

112. The method of claim 111 wherein the caspase is human interleukin-1β

converting enzyme.

113. A method of inhibiting the enzymatic activity of a viral or microbial cysteine protease comprising contacting the protease with an inhibitory amount of a compound of claim 74.

114. The method of claim 113 wherein the cysteine protease is human coronavirus.

115. The method of claim 113 wherein the microbial cysteine protease is gingipain.

116. A method of inhibiting the enzymatic activity of a protozoan cysteine protease comprising contacting the protease with an inhibitory amount of a compound of claim 95.

117. The method of claim 116 wherein the protozoan protease is a Trypanosoma, Schistosoma or Leishmania protease.

118. The method of claim 116 wherein the protozoan protease is a Plasmodium protease.

119. A method of inhibiting the enzymatic activity of cancer procoagulant comprising contacting the protease with an inhibitory amount of a compound of claim 1.

120. A method of inhibiting the enzymatic activity of cysteine proteases associated with apoptosis in pathological states comprising contacting the proteases with an inhibitory amount of a compound of claim 1.

121. A method of inhibiting cancer cell growth or tumor progression or tumor metastasis or invasion, by inhibiting the enzymatic activity of cysteine proteases associated with such growth or progession, comprising contacting such protease with an inhibitory amount of a compound of claim 1 or 2.

122. The method of claim 121 wherein said protease is cathepsin B or cathepsin L.

123. A method of inhibiting microbial cell or viral growth or reproduction by inhibiting the enzymatic activity of cysteine proteases associated with such growth or reproduction, comprising contacting such protease with an inhibitory amount of a compound of claim 1 or 2.

124. The method of claim 123 wherein the cysteine protease is hepatitis A virus 3C proteinase.

125. The method of claim 123 wherein the cysteine protease is hepatitis C virus endopeptidase 2.

126. The method of claim 123 wherein the cysteine protease is picomain 3C rhinovirus protease.

127. The method of claim 123 wherein the cysteine protease is foot and mouth disease virus L proteinase.

128. The method of claim 123 wherein the cysteine protease is encephalomyelitis virus endopeptidase 2.

129. The method of claim 123 wherein the cysteine protease is picornain 2A protease.

130. A method of treating the symptoms associated with allergic response by inhibiting the enzymatic activity of cysteine proteases associated with such response, comprising contacting such protease with an inhibitory amount of a compound of claim 1 or 2.

131. The method of claim 130 wherein the protease is Der p I.

132. A method of treating the symptoms associated with a neurodegenerative disorder by inhibiting the enzymatic activity of cysteine proteases associated with such disease, comprising contacting such protease with an inhibitory amount of a compound of claim 1 or 2.

133. The method of claim 132 wherein the neurodegenerative disorder is Alzheimer'"'"'s disease, Parkinson'"'"'s disease or multiple sclerosis.

134. The method of claim 133 wherein said disorder is a result of ischemic-reperfusion injury.

135. The method of claim 134 wherein the ischemic-reperfusion injury is stroke.

136. The method of claim 134 wherein the ischemic-reperfusion injury is myocardial infarction, transplantation, vascular injury or cardiovascular collapse or shock.

137. A method of treating the symptoms associated with inflammatory and degenerative diseases by inhibiting the enzymatic activity of cysteine proteases associated with such diseases, comprising contacting such protease with an inhibitory amount of a compound of claim 1 or 2.

138. The method of claim 137 wherein the inflammatory disease is an arthridity.

139. The method of claim 138 wherein the arthridity is rheumatoid arthiritis or osteoarthritis.

140. The method of claim 137 wherein the inflammatory disease is periodontal disease.

141. The method of claim 107 wherein the compound is [2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-phenylalanamide-(3R)-(isobutyl)succinic acid.

142. The method of claim 107 wherein the compound is:

Acetyl-L-leucyl-N-[1-[2-[5-phenyl]-1,3,4-oxadiazolyl]carbonyl]-4-(guanidino)-butyl-L-leucyl amide;

Acetyl-L-leucyl-N-[1-[3-[5-methyl]-1,2,4-oxadiazolyl]carbonyl]-ethyl-L-leucyl amide;

Acetyl-L-leucyl-N-[1-[3-[5-methyl]-1,2,4-oxadiazolyl]carbonyl]-4-(guanidino)-butyl-L-leucyl amide;

Acetyl-L-tyrosinyl-L-valyl-N-[1-[2-[(5-phenyl)-1,3,4-oxadiazolyl]carbonyl]-2-carboxy-ethyl]-L-alanine amide;

or

Acetyl-L-Aspartyl-Valyl-N-[1-[2-[(5-phenyl)-1,3,4-oxadiazolyl] carbonyl]-2-(carboxy)-ethyl]-L-glutamyl amide.

143. The method of claim 107 wherein the compound is

(t-butoxysuccinyl)-L-valyl-N-[1-[3-[5-(3-trifluoromethylbenzyl)-1,24-oxadiazolyl]carbonyl]-2-benzylidone]-L-prolinamide;

or

carboxysuccinyl-L-valyl-N-[1-[3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyllcarbonyl]-2-benzylidone]-L-prolinamide.

144. The method of claim 103 whereinthe compound is (benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.

145. A method of detecting or quantifying the activity of a cysteine protease in a pure sample, mixture or a biological fluid or tissue, comprising contacting said protease with a compound of claim 1 or 2.

146. A method of purifying a cysteine protease in a sample, comprising contacting said protease with a compound of claim 1 or 2.