Potent and selective ketoamide-based inhibitors of cysteine protease, cathepsin K

Journal of Medicinal Chemistry

Volumn 47, Issue 21, 2004, Pages 5049-5056

  Tavares, Francis X ^a   Deaton, David N ^a   Miller, Aaron B ^a   Miller, Larry R ^a   Wright, Lois L ^a   Zhou, Hui Qiang ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 BENZYL 1H PYRAZOL 5 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 CYCLOBUTYL 1H PYRAZOL 5 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 CYCLOHEXYL 1H PYRAZOL 5 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 CYCLOPENTYL 1H PYRAZOL 5 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 ETHYL 1H PYRAZOL 5 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 ISOBUTYL 1H PYRAZOL 5 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 ISOPROPYL 1H PYRAZOL 5 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 METHYL 1H PYRAZOL 3 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[(1 METHYL 1H PYRAZOL 5 YL)AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[[1 (3,3 DIMETHYLBUTYL) 1H PYRAZOL 5 YL]AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [[[1 (CYCLOPROPYLMETHYL) 1H PYRAZOL 5 YL]AMINO](OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [OXO (1H PYRAZOL 3 YLAMINO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [OXO [(3 PHENYL 1H PYRAZOL 5 YL)AMINO]ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOBUTYL)METHYL 1 [OXO[(1 PHENYL 1H PYRAZOL 5 YL)AMINO]ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOHEXYL)METHYL 1 [[(6 CHLORO 1H INDAZOL 3 YLAMINO)(OXO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOHEXYL)METHYL 1 [OXO (1H PYRAZOL 5 YLAMINO)ACETYL]PENTYLCARBAMIC ACID; (1 ETHYLCYCLOPENTYL)METHYL 1 [OXO (1H PYRAZOL 5 YLAMINO)ACETYL]PENTYLCARBAMIC ACID; 2,2 DIMETHYLBUTYL 1 [OXO (1H PYRAZOL 3 YLAMINO)ACETYL]PENTYLCARBAMIC ACID; AMIDE; CATHEPSIN K; CYSTEINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG POTENCY; DRUG SELECTIVITY; ENZYME INHIBITION; OSTEOPOROSIS;

AMIDES; CARBAMATES; CATHEPSINS; CYCLOBUTANES; CYCLOPENTANES; KETONES; MODELS, MOLECULAR; PYRAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 4744369975     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0400799     Document Type: Article

References (57)

1. (a) Marcus, R.; Feldman, D.; Kelsey, J. Osteoporosis, 1st ed.; Academic Press: New York, 1996.
2. (b) Baron, R. Anatomy and Ultrastructure of Bone. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 1st ed.; Favus, M. J., Ed.; American Society for Bone and Mineral Research: Kelseyville, CA, 1990; pp 3-9.
3. (a) Bromme, D.; Okamoto, K. Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary. Molecular cloning, sequencing and tissue distribution. Biol. Chem. Hoppe-Seyler 1985, 376, 379-384.
4. (b) Drake, F. H.; Dodds, R. A.; James, I. A.; Connor, J. R.; Debouck, C.; Richardson, S.; Lee-Rykaczewski, L.; Coleman, L.; Riemann, D.; Barthlow, R.; Hastings, G.; Gowen, M. Cathepsin K, but not cathepsins B, L or S is abundantly expressed in human osteoclasts. J. Biol. Chem. 1998, 271, 12511-12516.
5. (c) Littlewood-Evans, A.; Kokubo, T.; Ishibashi, O.; Inaoka, T.; Wlodarski, B.; Gallagher, J. A.; Bilbe, G. Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry. Bone 1997, 20, 81-86.
6. Shi, G.-P.; Chapman, H. A.; Bhairi, S. M.; DeLeeuw, C.; Reddy, V. Y.; Weiss, S. J. Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. FEBS Lett. 1995, 357, 129-134.
7. Inui, T.; Ishibashi, O.; Inaoka, T.; Origane, Y.; Kumegawa, M.; Kokubo, T.; Yamaura, T. Cathepsin K antisense oligodeoxy-nucleotide inhibits osteoclastic bone resorption. J. Biol. Chem. 1997, 272, 8109-8112.
8. (a) Gelb, B. D.; Moissoglu, K.; Zhang, J.; Martignetti, J. A.; Bromme, D.; Desnick, R. J. Cathepsin K: isolation and characterization of the murine cDNA and genomic sequence, the homologue of the human pycnodysostosis gene. Biochem Mol. Med. 1998, 59, 200-206.
9. (b) Johnson, M. R.; Polymeropoulos, M. H.; Vos, H. L.; Oritz de Luna, R. I.; Francomano, C. A. A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. Genome Res. 1986, 6, 1050-1055.
10. (c) Gelb, B. D.; Shi, G.-P.; Chapman, H. A.; Desnick, R. J. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 1988, 273, 1236-1238.
11. Motyckova, G.; Fisher, D. Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. Curr. Mol. Med. 2002, 2, 407-421.
12. (a) Saftig, P.; Hunziker, E.; Wehmeyer, O.; Jones, S.; Boyde, A.; Rommerskirch, W.; Detlev, J. D.; Schu, P.; von Figura, K. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin K deficient mice. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 13453-13458.
13. (b) Gowen, M.; Lazner, F.; Dodds, R.; Kapadia, R.; Field, J.; Tavaria, M.; Bertoncello, I.; Drake, F.; Zavarselk, S.; Tellis, I.; Hertzog, P.; Debouck, C.; Kola, I. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J. Bone Miner. Res. 1989, 14, 1654-1663.
14. (a) James, I. E.; Marquis, R. W.; Blake, S. M.; Hwang, S. M.; Gress, C. J.; Ru, Y.; Zembryki, D.; Yamashita, D. S.; McQueney, M. S.; Tomaszek, T. A.; Oh, H. J.; Gowen, M.; Veber, D. F.; Lark, M. W. Potent and selective cathepsin L inhibitors do not inhibit osteoclast resorption in vitro. J. Biol. Chem. 2001, 276, 11507-11511.
15. (b) Stroup, G. B.; Lark, M. V.; Veber, D. F.; Bhattacharya, A.; Blake, S.; Dare, L. C.; Erhard, K. F.; Huffman, S. J.; James, I. E.; Marquis, R. W.; Ru, Y.; Vasko-Moser, J. A.; Smith, B. R.; Tomaszek, T.; Gowen, M. Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J. Bone Miner. Res. 2001, 16, 1739-1746.
16. (c) Li, Z.; Yasuda, Y.; Li, W.; Bogyo, M.; Katz, N.; Gordon, R. E.; Fields, G. B.; Bromme, D. Regulation of collagenase activities of human cathepsins by glycosaminoglycans. J. Biol. Chem. 2004, 279, 5470-5479.
17. (a) Delaisse, J. M.; Boyde, A.; Maconnachie, E.; Ali, N. N.; Sear, C. H. J.; Eeckhout, Y.; Levy, M. The effect of inhibitors of cysteine-proteinases and collagenase on the resorptive activity of isolated osteoclasts. Bone 1987, 8, 305-313.
18. (b) Everts, V.; Beertsen, W.; Schroder, R. Effects of the proteinase inhibitors leupeptin and E-64 on osteoclastic bone resorption. Calcif. Tissue Int. 1988, 43, 172-178.
19. (a) Turk, B.; Turk, D.; Turk V. Review. Lysosomal cysteine proteases: more than scavengers. Biochim. Biophys. Acta. 2000, 1477, 98-111.
20. (b) Buhling F.; Fengler A.; Brandt W.; Welte T.; Ansorge S.; Nagler D K Review: Novel cysteine proteases of the papain family. Adv. Exp. Med. Biol. 2000, 477, 241-254.
21. (c) Hashimoto, Y.; Kakegawa, H.; Narita, Y.; Hachiya, Y.; Hayakawa, T.; Kos, J.; Turk, V.; Katunuma, N. Significance of cathepsin B accumulation in synovial fluid of rheumatoid arthritis. Biochem. Biophys. Res. Commun. 2001, 283, 334-339.
22. Szpaderska, A. M.; Frankfater, A. An intracellular form of Cathepsin B contributes to invasiveness in cancer. Cancer Res. 2001, 61, 3493-3500.
23. (e) Greenspan, P. D.; Clark, K. L.; Tommasi, R. A.; Cowen, S. D.; McQuire, L. W.; Parley, D. L.; Van Duzer, J. H.; Goldberg, R. L.; Zhou, H.; Du, Z.; Fitt, J. J.; Coppa, D. E.; Fang, Z.; Macchia, W.; Zhu, L.; Michael, P. Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design. J. Med. Chem. 2001, 44, 4524-4534.
24. Turk, V.; Turk, B.; Turk, D. Review: Lysosomal cysteine proteases: facts and opportunities. EMBO J. 2001, 20, 4629-4633.
25. (a) Palmer, J. T.; Rasnick, D.; Haus, J. L.; Bromme, D. Vinyl sulfones as mechanism based cysteine protease inhibitors. J. Med. Chem. 1995, 38, 3193-3196.
26. (b) Bromme, D.; Klaus, J. L.; Okamoto, K.; Rasnick, D.; Palmer, J. T. Peptidyl vinyl sulfones: A new class of potent and selective cysteine protease inhibitors. Biochem. J. 1936, 315, 85-89.
27. (c) Dai, Y.; Hedstrom, L.; Abeles, R. Inactivation of cysteine proteases by (acyloxy) methyl ketones using S′-P′ interactions. Biochemistry 2000, 39, 6498-6502.
28. (a) Yamashita, D. S.; Dodds, R. A. Cathepsin K and the design of inhibitors of cathepsin K. Curr. Pharm. Des. 2000, 6, 1-24.
29. (b) Leung, D.; Abbenante, G.; Fairlie, D. Protease inhibitors: current status and future prospects. J. Med. Chem. 2000, 43, 305-341.
30. (b) Schirmeister, T.; Otto, H. Cysteine proteases and their inhibitors. Chem Rev. 1997, 97, 133-171.
31. (a) Votta, B. J.; Levy, M. A.; Badger, A.; Bradbeer, J.; Dodds, R. A.; James, I. E.; Thompson, S.; Bossard, M. J.; Carr, T.; Conner, J. R.; Tomaszek, T. A.; Szewczuk, L.; Drake, F. H.; Veber, D. F.; Gowen, M. Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo. J. Bone Miner. Res. 1997, 12, 1396-1406.
32. (b) Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T. Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J. Med. Chem. 1998, 41, 4301-4308.
33. Karanewsky, D. S.; Bai, X.; Linton, S. D.; Krebs, J. F.; Wu, J.; Pham, B.; Tomaselli, K. J. Conformationally constrained inhibitors of caspase-1 (interleukin-1α converting enzyme) and of the human CED-3 homologue caspase-3 (CPP32, apopain). Bioorg. Med. Chem. Lett. 1998, 8, 2757-2762.
34. 1 SAR of aldehyde cathepsin K inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 275-278.
35. 13C NMR evidence for a thioimidate ester adduct. J. Am. Chem. Soc. 1986, 108, 1350-1351.
36. (b) Brisson, J.-R.; Carey, P. R.; Storer, A. C.; Benzoylamidoacetonitrile is bound as a thioimidate in the active site of papain. J. Biol. Chem. 1986, 261, 9087-9089.
37. (c) Liang, T.-C.; Abeles, R. H. Inhibition of papain by nitriles: mechanistic studies using NMR and kinetic measurements. Arch. Biochem. Biophys. 1987, 252, 626-634.
38. (a) Ando, R.; Morinaka, Y. A new class of proteinase inhibitor. Cyclopropenone-containing inhibitor of papain. J. Am. Chem. Soc. 1993, 115, 1174-1175.
39. (b) Ando, R.; Sakaki, T.; Morinaka, Y.; Takahashi, C.; Tamao, Y.; Yoshii, N.; Katayama, S.; Saito, K.; Tokuyama, H.; Isaka, M.; Nakamura, E. Cyclopropenone-containing cysteine proteinase inhibitors. Synthesis and enzyme inhibitory activities. Bioorg. Med. Chem. 1999, 7, 571-579.
40. (a) Majalli, A. M. M.; Chapman, K. T.; MacCoss, M.; Thornberry, N. A.; Peterson, E. P. Activated ketones as potent reversible inhibitors of interleukin-1α converting enzyme. Bioorg. Med. Chem. Lett. 1994, 4, 1965-1968.
41. (b) Yamashita, D. S.; Smith, W. W.; Zhao, B.; Janson, C. A.; Tomaszek, T. A.; Bossard, M. A.; Levy, M. A.; Oh, H.-J.; Carr, T. J.; Thompson, S. T.; Ijames, C. F.; Carr, S. A.; McQueney, M.; D'Alessio, K. J.; Amegadzie, B. Y.; Hanning, C. R.; Abdel-Meguid, S.; DesJarlais, R. L.; Gleason, J. G.; Veber, D. F. Structure and design of potent and selective cathepsin K inhibitors. J. Am. Chem. Soc. 1997, 119, 11351-11352.
42. (c) DesJarlais, R. L.; Yamashita, D. S.; Oh, H.-J.; Uzinskas, I. N.; Erhard, K. F.; Allen, A. C.; Haltwanger, R. C.; Zhao, B.; Smith, W. W.; Abdel-Meguid, S. S.; D'Allesio, K.; Janson, C. A.; McQueney, M. S.; Tomaszek, T. A.; Levy, M. A.; Veber, D. F. Use of X-ray cocrystal structures and molecular modeling to design potent and selective non-peptide inhibitors of cathepsin K. J. Am. Chem. Soc. 1998, 120, 9114-9115.
43. (d) Marquis, R. W.; Ru, Y.; LoCastro, S. M.; Zeng, J.; Yamashita, D. S.; Oh, H.-J.; Erhard, K F.; Davis, L. D.; Tomaszek, T. A.; Tew, D.; Salyers, K.; Proksch, J.; Ward, K.; Smith, B.; Levy, M.; Cummings, M. D.; Haltiwanger, R. C.; Trescher, G.; Wang, B.; Hemling, M. E.; Quinn, C. J.; Cheng, H.-Y.; Lin, F.; Smith, W. W.; Janson, C. A.; Zhao, B.; McQueney, M. S.; D'Alessio, K.; Lee, C.-P.; Marzulli, A.; Dodds, R. A.; Blake, S.; Hwang, S.-M.; James, I. E.; Gress, C. J.; Bradley, B. R.; Lark, M. W.; Gowen, M.; Veber, D. F. Azepanone-based inhibitors of human and rat cathepsin K. J. Med. Chem. 2001, 44, 1380-1395.
44. (a) Hu, L.-Y.; Abeles, R. H. Inhibition of cathepsin B and papain by peptidyl α-keto esters, α-keto amides α-diketones and α-keto acids. Arch. Biochem. Biophys. 1890, 281, 271-274.
45. (b) Li, Z.; Patil, G. S.; Golubski, Z. E.; Hori, H.; Tehrani, K.; Foreman, J. E.; Eveleth, D. D.; Bartus, R. T.; Powers, J. C. Peptide α-keto ester, α-keto amide, and α-keto acid inhibitors of calpains and other cysteine proteases. J. Med. Chem. 1993, 36, 3472-3480.
46. (c) Harbeson, S. L.; Abelleira, S. M.; Akiyama, A.; Barrett, R., III; Carroll R. M. Straub, J. A. Tkacz, J. N.; Wu, C.; Musso, G. F. Stereospecific synthesis of peptidyl α-keto amides as inhibitors of calpain. J. Med. Chem. 1994, 37, 2918-2929.
47. Altmann E.; Renaud, J.; Green, J.; Parley, D.; Cutting, B.; Jahnke, W. Arylaminoethyl amides as novel noncovalent cathepsin K inhibitors. J. Med. Chem. 2002, 45, 2352-2354.
48. Cacciola, J.; Fevig, J. M.; Stouten, P. F. W.; Alexander, R. S.; Knabb, R. M.; Wexler, R. R. Synthesis and activity studies of conformationally restricted α-ketoamide factor Xa inhibitors. Bioorg. Med. Chem. Lett. 2000, 10, 1253-1256.
49. (a) Tavares, F. X.; Boncek, V.; Deaton, D. N.; Hassell, A. M.; Long, S. T.; Miller, A. B.; Payne, A. A.; Miller, L. R.; Shewchuk, L. M.; Wells-Knecht, K.; Willard, D. H.; Wright, L. L.; Zhou, H.-Q. Design of potent, selective, and orally bioavailable inhibitors of cysteine protease cathepsin K. J. Med. Chem. 2004, 47, 588-599.
50. (b) Catalano, J. G.; Deaton, D. N.; Long, S. T.; McFadyen, R. B.; Miller, L. R.; Payne, A.; Wells-Knecht, K. J.; Wright, L. L. Design of small molecule ketoamide-based inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2004, 14, 719-722.
51. Rosenthal, K.; Karlström, A.; Undén, A. The 2,4-dimethylpent-3-yloxycarbonyl (Doc) group as a new, nucleophile-resistant protecting group for tyrosine in solid-phase peptide synthesis. Tetrahedron Lett. 1997, 38, 1075-1078.
52. Wasserman, H. H.; Ho, W.-B. (Cyanomethylene)phosphoranes as novel carbonyl 1,1-dipole synthons: An efficient synthesis of α-keto acids, esters, and amides. J. Org. Chem. 1994, 59, 4364-4366.
53. Dorgan, R. J.; Parrick, J.; Hardy, C. R. The preparation of 1-protected-1H-pyrazolo[3,4-b]pyridines and attempts to move the 1-substituent. J. Chem. Soc., Perkin Trans. 1 1980, 938-942.
54. Frigola, J.; Colombo, A.; Pares, J.; Martinez, L.; Sagarra, R.; Roser, R. Synthesis, structure and inhibitory effects on cyclooxygenase, lipoxygenase, thromboxane synthetase and platelet aggregation of 3-amino-4,5-dihydro-1H- pyrazole derivatives. Eur. J. Med. Chem. Chim. Ther. 1989, 24, 435-446.
55. Ege, G.; Franz, H. Reactions with diazoazoles Part VI. Unequivocal synthesis of 3-mthyl-3H-azolotetrazoles. J. Heterocycl. Chem. 1982, 18, 1267-1273.
56. (a) Setti, E. L.; Davis, D.; Chung, T.; McCarter, J. 3,4-Disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P2 elements for selectivity. Bioorg. Med. Chem. Lett. 2003, 13, 2051-2053.
57. (b) Kim, T.-S.; Hague, A. B.; Lee, T. I.; Lian, B.; Tegley, C. M.; Wang, X.; Burgess, T. L.; Qian, Y.-X.; Ross, S.; Tagari, P.; Lin, C.-H.; Mayeda, C.; Dao, J.; Jordan, S.; Mohr, C.; Cheetham, J.; Viswanadhan, V.; Tasker, A. S. Bioorg. Med. Chem. Lett. 2004, 14, 87-90.