A novel class of nonpeptidic biaryl inhibitors of human cathepsin K

Journal of Medicinal Chemistry

Volumn 46, Issue 17, 2003, Pages 3709-3727

  Robichaud, Joël ^a   Oballa, Renata ^a   Prasit, Peppi ^a   Falgueyret, Jean Pierre ^a   Percival, M David ^a   Wesolowski, Gregg ^b   Rodan, Sevgi B ^b   Kimmel, Donald ^b   Johnson, Colena ^b   Bryant, Cliff ^c   Venkatraman, Shankar ^c   Setti, Eduardo ^c   Mendonca, Rohan ^c   Palmer, James T ^c  

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

^b MERCK RESEARCH LABORATORIES   (United States)

^c Celera ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; AMINOACETONITRILE; BIOLOGICAL MARKER; CATHEPSIN B; CATHEPSIN K; CATHEPSIN K INHIBITOR; CATHEPSIN S; COLLAGEN DERIVATIVE; COLLAGEN TYPE 1; CYSTEINE PROTEINASE; CYSTEINE PROTEINASE INHIBITOR; DIPEPTIDE; ENZYME INHIBITOR; N (CYANOMETHYL) 4 METHYL 2 [4' (1 PIPERAZINYL)(1,1' BIPHENYL) 3 YL]PENTANAMIDE; NITRILE; PEPTIDE DERIVATIVE; PHENYL GROUP; POLYCYCLIC AROMATIC HYDROCARBON DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE TISSUE; BONE TURNOVER; CATTLE; CHEMICAL BOND; CHEMICAL REACTION; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG HYDROLYSIS; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME ASSAY; ENZYME INHIBITION; ENZYME MECHANISM; FEMALE; HUMAN; IC 50; IN VITRO STUDY; IN VIVO STUDY; MOLECULAR WEIGHT; NONHUMAN; OSTEOCLAST; OSTEOLYSIS; OSTEOPOROSIS; OVARIECTOMY; PHARMACOKINETICS; PROTEIN URINE LEVEL; RABBIT; REACTION ANALYSIS; RHESUS MONKEY; STRUCTURE ANALYSIS; SUBSTITUTION REACTION; TECHNIQUE;

ANIMALS; BIOLOGICAL MARKERS; BIPHENYL COMPOUNDS; BONE AND BONES; BONE RESORPTION; CATHEPSIN B; CATHEPSINS; CATTLE; COLLAGEN; COLLAGEN TYPE I; CYSTEINE ENDOPEPTIDASES; HUMANS; MACACA MULATTA; NITRILES; OSTEOCLASTS; OVARIECTOMY; PEPTIDES; PIPERAZINES; PROTEASE INHIBITORS; RABBITS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TIME FACTORS;

EID: 0041565245     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0301078     Document Type: Article

References (34)

1. Peck, W. A.; Burckhardt, P.; Christiansen, C.; Fleisch, H. A.; Genant, H. K.; Gennari, C.; Martin, T. J.; Martini, L.; Morita, R.; Ogata, E.; Rapado, A. ; Shulman, L. E.; Stern, P. H.; Young, R. T. T.; Barrett-Connor, E.; Brandi, M. L.; Chesnut, C. H.; Delmas, P. D.; Heaney, R. P.; Johnston, C. C.; Kanis, J. A. ; Lindsay, R.; Meunier, P. J.; Papapoulos, S. E.; Reginster, J. Y.; Riggs, B. L.; Riis, B. J.; Seeman, E.; Wasnich, R. D. Consensus development conference: diagnosis prophylaxis and treatment of osteoporosis. Am. J. Med. 1993, 94, 646-650.
2. Bromme, D.; Okamoto, K.; Wang, B. B.; Biroc, S. Human Cathepsin O2, a matrix protein-degrading cysteine protease expressed in osteoclasts. J. Biol. Chem. 1996, 271, 2126-2132.
3. Bossard, M. J.; Tomaszek, T. A.; Thompson, S. K.; Amegadzie, B. Y.; Hanning, C. R.; Jones, C.; Kurdyla, J. T.; McNulty, D. E.; Drake, F. H.; Gowen, M.; Levy, M. A. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J. Biol. Chem. 1996, 271, 12517-12524.
4. Tezuka, K.; Tezuka, Y.; Maejima, A.; Sato, T.; Nemoto, K.; Kamioka, H.; Hakeda, Y.; Kumegawa, M. Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J. Biol. Chem. 1994, 269, 1106-1109.
5. Turk, B.; Turk, D.; Turk, V Lysosomal cysteine proteases: more than scavengers. Biochim. Biophys. Acta 2000, 1477, 98-111.
6. Drake, F. H.; Dodds, R. A.; James, I. E.; Connor, J. R.; Debouck, C.; Richardson, S.; Lee-Rykaczewski, E.; Coleman, L.; Rieman, D.; Barthlow, R.; Hastings, G.; Gowen, M. Cathepsin K, but not Cathepsin B, L, or S, is abundantly expressed in human osteoclasts. J. Biol. Chem. 1996, 271, 12511-12516.
7. Kirschke, H.; Brömme, D.; Wiederanders, B. Cathepsin S, a lysosomal cysteine protease. In Proteolysis and Protein Turnover; Bond, J. S., Barret, A. J., Eds.; Portland Press: London and Chapel Hill, 1993; pp 33-37.
8. Shi, G. P.; Villadangos, J. A.; Dranoff, G.; Small, C.; Gu, L.; Haley, K. J.; Riese, R.; Ploegh, H. L.; Chapman, H. A.; Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 1999, 10 (2), 197-206.
9. Linnevers, C.; Smeekens, S. P.; Bromme, D. Human cathepsin W, a putative cysteine protease predominantly expressed in CD8+ T-lymphocytes. FEBS Lett. 1997, 405 (3), 253-259.
10. Hernandez, A. A.; Roush, W. Recent advances in the synthesis, design and selection of cysteine inhibitors. Curr. Opin. Chem. Biol. 2002, 6, 459-465.
11. Lecaille, F.; Kaleta, J.; Bromme, D. Human and parasitic papainlike cysteine proteases: their role in physiology and pathology and recent developments in inhibitor design. Chem. Rev. 2002, 102 (12), 4459-4488.
12. Bryant, C. M.; Palmer, J. T.; Rydzewski, R. M.; Setti, E. L.; Tian, Z.-Q.; Venkatraman, S. Novel compounds and compositions as protease inhibitors. World Patent 2000/55126, Chem. Abstr. 2000, 133, 252050.
13. Gabriel, T.; Pech, M.; Rodriguez Sarmiento, R. M. β-amino acid nitrile derivatives useful for the treatment of diseases which are associated with cysteine proteases. World Patent 2001/96285, Chem. Abstr. 2001, 136, 53544.
14. Missbach, M. Preparation of dipeptide cathepsin K inhibitors. World Patent 2001/58886, Chem. Abstr. 2001, 135, 180786.
15. Altmann, E.; Betschart, C.; Gohda, K.; Horiuchi, M.; Lattmann, R.; Missbach, M.; Sakaki, J.; Takai, M.; Teno, N.; Cowen, S. D.; Greenspan, P. D.; McQuire, L. W.; Tommasi, R. A.; Van Duzer, J. H. Dipeptide nitriles. World Patent 9924460, Chem. Abstr. 1999, 130, 352553.
16. Greenspan, P. D.; Clark, K. L.; Tommasi, R. A.; Cowen, S. D.; McQuire, L. W.; Farley, 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.; Capparelli, M. P.; Goldstein, R.; Wigg, A. M.; Doughty, J. R.; Bohacek, R. S.; Knap, A. K. Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design. J. Med. Chem. 2001, 44, 4524-4534.
17. Ward, Y. D.; Thomas, D. S.; Frye, L. L.; Cywin, C. L.; Morwick, T.; Emmanuel, M. J.; Zindell, R.; McNeil, D.; Bekkali, Y.; Giradot, M.; Hrapchak, M.; DeTuri, M.; Crane, K.; White, D.; Pav, S.; Wang, Y.; Hao, M.-H.; Grygon, C. A.; Labadia, M. E.; Freeman, D. M.; Davidson, W.; Hopkins, J. L.; Brown, M. L.; Spero, D. M. Design and synthesis of dipeptide nitriles as reversible and potent cathepsin S inhibitors. J. Med. Chem. 2002, 45, 5471-5482.
18. Suzue, S.; Irikura, T. Studies on hepatic agents. I. Synthesis of aminoacyl (and hydroxyacyl) aminoacetonitriles. Chem. Pharm. Bull. 1968, 16, 1417-1432.
19. Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.; Grabowski, E. J. J. α-Hydroxy esters as chiral reagents: asymmetric synthesis of 2-arylpropionic acids. J. Am. Chem. Soc. 1989, 111, 7650-7651.
20. Huntress, E. H.; Pfister, K., III. The conversion of 2-phenyl-4-chloromethylthiazole to 2-phenyl-4-hydroxymethyl-5-chlorothiazole. J. Am. Chem. Soc. 1943, 65, 1667-1669.
21. Falgueyret, J. P.; Oballa, R. M.; Okamoto, O.; Wesolowski, G.; Aubin, Y. ; Rydzewski, R. M.; Prasit, P.; Riendeau, D.; Rodan, S. B.; Percival, M. D. Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L. J. Med. Chem. 2001, 44 (1), 94-104.
22. DesJarlais, R. L.; Yamashita, D. S.; Oh, H.-J.; Uzinskas, I. N.; Erhard, K. F.; Allen, A. C.; Haltiwanger, R. C.; Zhao, B.; Smith, W. W.; Abdel-Meguid, S. A.; D'Alessio, 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.
23. Gour-Salin, B. J.; Storer, A. C.; Castelhano, A.; Krantz, A.; Robinson, V. Inhibition of papain by peptide nitriles: Reactions of external nucleophiles with the thioimidate ester adduct. Enzyme Microb, Technol. 1991, 13, 408-411.
24. Dufour, E.; Storer, A. C.; Menard, R. Engineering nitrile hydratase activity into a cysteine protease by a single mutation. Biochemistry 1995, 34, 4 (50), 16382-16388.
25. Bossard, M. J.; Tomaszek, T. A.; Levy, M. A.; Ijames, C. F.; Huddleston, M. J.; Briand, J.; Thompson, S.; Halpert, S.; Veber, D. F.; Carr, S. A.; Meek, T. D.; Tew, D. G. Mechanism of inhibition of cathepsin K by potent, selective 1,5-diacylcarbohydrazides: a new class of mechanism-based inhibitors of thiol proteases. Biochemistry 1999, 38, 8 (48), 15893-15902.
26. Christgau, S.; Bitsch-Jensen, O.; Hanover-Bjarnason, N.; Gamwell-Henriksen, E.; Qvist, P.; Alexandersen, P.; Bang-Henriksen, D. Serum CrossLaps for monitoring the response in individuals undergoing antiresorptive therapy. Bone 2000, 26, 505-511.
27. Joens, D. H. J. Chem. Soc. (C) 1971, 132-137.
28. Prepared from commercially available 3-morpholinophenol according to Kotsuki, H.; Kobayashi, S.; Suenaga, H.; Nishizawa, H. High-pressure organic chemistry; XI. A new convenient synthesis of aromatic amines from activated phenols. Synthesis 1990, 12, 1145-1147.
29. Prepared from commercially available 2-morpholinophenol according to ref 28.
30. Poindexter, G. S.; Bruce, M. A.; LeBoulluec, K. L.; Monkovic, I. Use of 2-oxazolidinones as latent aziridine equivalents. III. Preparation of N-substituted piperazines. Tetrahedron Lett. 1994, 35, 7331-7334.
31. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. A Highly Active Catalyst for Palladium-Catalyzed Cross-Coupling Reactions: Room-Temperature Suzuki Couplings and Amination of Unactivated Acyl Chlorides. J. Am. Chem. Soc. 1998, 120, 9722-9723.
32. Linnevers, C. J.; McGrath, M. E.; Armstrong, R.; Mistry, F. R.; Barnes, M. G.; Klaus, J. L.; Palmer, J. T.; Katz, B. A.; Bromme, D. Expression of human cathepsin K in Pichia pastoris and preliminary crystallographic studies of an inhibitor complex. Protein Sci. 1997, 6 (4), 919-921.
33. Bromme, D.; McGrath, M. E. High level expression and crystallization of recombinant human cathepsin S. Protein Sci. 1996, 5 (4), 789-791.
34. Izquierdo-Martin, M.; Stein, R. L. Transition-state structural features for the association of metalloproteases with phosphorus-containing inhibitors. J. Am. Chem. Soc. 1992, 114, 1527-1528.