Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis

Journal of Medicinal Chemistry

Volumn 51, Issue 20, 2008, Pages 6410-6420

  Robichaud, Jöel ^a   Black, W Cameron ^a   Thérien, Michel ^a   Paquet, Julie ^a   Oballa, Renata M ^a   Bayly, Christopher I ^a   McKay, Daniel J ^a   Wang, Qingping ^a   Isabel, Elise ^a   Léger, Serge ^a   Mellon, Christophe ^a   Kimmel, Donald B ^b   Wesolowski, Gregg ^b   Percival, M David ^a   Massé, Frédéric ^a   Desmarais, Sylvie ^a   Falgueyret, Jean Pierre ^a   Crane, Sheldon N ^a  

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,2,2 TRIFLUOROETHYL DERIVATIVE; 5,5 DICHLORO N (1 CYANOCYCLOPROPYL) 2 [4 [4 (METHYLSULFONYL)PHENYL] 1 (2,2,2 TRIFLUOROETHYL) 1H PYRAZOL 3 YL]CYCLOHEXANECARBOXAMIDE; 5,5 DIFLUORO N (1 CYANOCYCLOPROPYL) 2 [4 [4 (METHYLSULFONYL)PHENYL] 1 (2,2,2 TRIFLUOROETHYL) 1H PYRAZOL 3 YL]CYCLOHEXANECARBOXAMIDE; CATHEPSIN K INHIBITOR; CYCLOHEXANE DERIVATIVE; CYCLOHEXANECARBOXAMIDE DERIVATIVE; DIMETHYL SULFONE; FLUORINE DERIVATIVE; HETEROCYCLIC COMPOUND; MK 1256; N METHYLPYRAZOLE DERIVATIVE; NITRILE; PYRROLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHEMICAL REACTION; CONTROLLED STUDY; DEMETHYLATION; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG METABOLISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME ASSAY; EXPERIMENTAL MODEL; FEMALE; HUMAN; IC 50; MONKEY; NONHUMAN; OSTEOLYSIS; OSTEOPOROSIS; RAT; STRUCTURE ANALYSIS;

ANIMALS; CATHEPSINS; CYSTEINE PROTEINASE INHIBITORS; DISEASE MODELS, ANIMAL; DOGS; FEMALE; KINETICS; MACACA MULATTA; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NITRILES; OSTEOPOROSIS; PYRAZOLES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES;

EID: 54549088956     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800610j     Document Type: Article

References (32)

1. (a) Gasser, J. The Relative Merits of Anabolics versus Anti-Resorptive Compounds: Where Our Targets Should Be, and Whether We Are Addressing Them. Curr. Opin. Pharmacol. 2006, 6, 313-318.
2. (b) Bonnick, S. L. Osteoporosis in Men and Women. Clin. Cornerstone 2006, 8, 28-39.
3. (a) Henriksen, K.; Tanko, L. B.; Qvist, P.; Delmas, P. D.; Christiansen, C.; Karsdal, M. A. Assessment of Osteoclast Number and Function: Application in the Development of New and Improved Treatment Modalities for Bone Diseases. Osteoporosis Int. 2007, 18, 681-685.
4. (b) Seeman, E.; Delmas, P. D. Bone Quality. The Material and Structural Basis of Bone Strength and Fragility. N. Engl. J. Med 2006, 354, 2250-2261.
5. (a) Mathoo, M. R.; Becker, L.; Kumbhare, D.; Adachi, J. D. Therapeutic Advances in the Treatment of Osteoporosis. Expert Opin. Ther. Pat. 2007, 17, 277-285.
6. (b) Grey, A. Emerging Pharmacologic Therapies for Osteoporosis. Expert Opin. Emerging Drugs 2007, 12, 493-508.
7. Troen, B. R. The Role of Cathepsin K in Normal Bone Resorption. Drug News Perspect. 2004, 17, 19-28.
8. (a) Gauthier, J.-Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L.; Falgueyret, J.-P.; Kimmel, D.; Lamontagne, S.; Léger, S.; LeRiche, T.; Li, C.-S.; Massé, F.; McKay, D. J.; Nicoll-Griffith, D.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Riendeau, D.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Thérien, M.; Truong, V.-L.; Venuti, M.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. The Discovery of Odanacatib (MK-0822), a Selective Inhibitor of Cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18, 923-928.
9. (b) Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.-P.; Gauthier, J. Y.; Kimmel, D. B.; Léger, S.; Massé, F.; McGrath, M. E.; Mckay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Thérien, M.; Truong, V.-L.; Wesolowski, G.; Zamboni, R.; Black, W. C. Identification of a Potent and Selective Non-Basic Cathepsin K Inhibitor. Bioorg. Med. Chem. Lett. 2006, 16, 1985-1989.
10. 3 Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K. J. Med. Chem. 2005, 48, 7520-7534.
11. (a) Crane, S. N.; Black, W. C.; Palmer, J. T.; Davis, D. E.; Setti, E.; Robichaud, J.; Paquet, J.; Oballa, R. M.; Bayly, C. I.; McKay, D. J.; Somoza, J. R.; Chauret, N.; Seto, C.; Scheigetz, J.; Wesolowski, G.; Masse, F.; Desmarais, S.; Ouellet, M. β-Substituted Cyclohexanecarboxamide: A Nonpeptidic Framework for the Design of Potent Inhibitors of Cathepsin K. J. Med. Chem. 2006, 49, 1066-1079.
12. (b) Robichaud, J.; Bayly, C. I.; Black, W. C.; Desmarais, S.; Léger, S.; Massé, F.; McKay, D. J.; Oballa, R. M.; Paquet, J.; Percival, M. D.; Truchon, J.-F.; Wesolowski, G.; Crane, S. N. β-Substituted Cyclohexanecarboxamide Cathepsin K Inhibitors: Modification of the 1,2-Disubstituted Aromatic Core. Bioorg. Med. Chem. Lett. 2007, 17, 3146-3151.
13. (a) Falgueyret, J.-P.; Oballa, R.; 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, 94-104.
14. 50 values would be expected to be very similar (see refs 10a and 19b).
15. Wright, J. D.; Boudinot, F. D.; Ujhelyi, M. R. Measurement and Analysis of Unbound Drug Concentrations. Clin. Pharmacokinet. 1996, 30, 445-462.
16. Schechter, I.; Berger, A. On the Size of the Active Site in Proteases. Biochem. Biophys. Res. Commun. 1967, 27, 157-162.
17. 157). See ref 10b for expression and purification procedures. Cyclohexanecarboxamide based inhibitors were equipotent against humanized-rabbit and human Cat K.
18. (b) Robichaud, J.; Oballa, R.; Prasit, P.; Falgueyret, J.-P.; Percival, M. D.; Wesolowski, G.; Rodan, S. B.; Kimmel, D.; Johnson, C.; Bryant, C.; Venkatraman, S.; Setti, E.; Mendonca, R.; Palmer, J. T. A Novel Class of Nonpeptidic Biaryl Inhibitors of Human Cathepsin K. J. Med. Chem. 2003, 46, 3709-3737.
19. Case, D. A.; Pearlman, D. A.; Caldwell, J. W.; Cheatham, T. E., III.; Ross, W. S.; Simmerling, C. L.; Darden, T. A.; Merz, K. M.; Stanton, R. V.; Cheng, A. L.; Vincent, J. J.; Crowley, M.; Tsui, V.; Radmer, R. J.; Duan, Y.; Pitera, J.; Massova, I.; Seibel, G. L.; Singh, U. C.; Weiner, P. K.; Kollman, P. A. AMBER, version 6; University of California: San Francisco, CA, 1999.
20. Hale, K. J.; Jogiya, N.; Manaviazar, S. Monamycin Synthetic Studies Part 1. An Enantiospecific Total Synthesis of (3S,5S)-5- Hydroxypiperazic Acid from D-Mannitol. Tetrahedron Lett. 1998, 39, 7163-7166.
21. (a) Armstrong, A.; Davies, N. G. M.; Martin, N. G.; Rutherford, A. P. Evaluation of Asymmetric Diels-Alder Approaches for the Synthesis of the Cyclohexene Subunit of CP-225,917 and CP-263,114. Tetrahedron Lett. 2003, 44, 3915-3918.
22. (b) Evans, D. A.; Chapman, K. T.; Bisaha, J. Asymmetric Diels-Alder Cycloaddition Reactions with Chiral α,β-Unsaturated N-Acyloxazolidinones. J. Am. Chem. Soc. 1988, 110, 1238-1256.
23. Damon, R. E.; Coppola, G. M. Cleavage of N-Acyl Oxazolidinones. Tetrahedron Lett. 1990, 31, 2849-2852.
24. Takeda, T.; Sasaki, R.; Yamauchi, S.; Fujiwara, T. Transformation of Ketones and Aldehydes to gem-Dihalides via Hydrazones using Copper (II) Halides. Tetrahedron 1997, 53, 557-566.
25. Drayton, C. J. In Comprehensive Heterocyclic Chemistry, 1st ed; Pergamon: Oxford, U.K., 1984.
26. Radiolabeled 31 was prepared by using tritium instead of hydrogen gas in step d of Scheme 4.
27. (a) Lohr, J. W.; Willsky, G. R.; Acara, M. A. Renal Drug Metabolism. Pharmacol. Rev. 1998, 50, 107-141.
28. (b) Nicoll-Griffith, D. A.; Gupta, N.; Twa, S. P.; Williams, H.; Trimble, L. A.; Yergey, J. A. Verlukast (MK-0679) Conjugation with Glutathione by Rat Liver and Kidney Cytosols and Excretion in the Bile. Drug Metab. Dispos. 1995, 23, 1085-1093.
29. (a) Binkley, N.; Kimmel, D.; Bruner, J.; Haffa, A.; Davidowitz, B.; Meng, C.; Schaffer, V.; Green, J. Zolendonate Prevents the Development of Absolute Osteopenia following Ovariectomy in Adult Rhesus Monkeys. J. Bone Miner. Res. 1998, 13, 1775-1782.
30. (b) Guay, J.; Riendeau, D.; Mancini, J. A. Cloning and Expression of Rhesus Monkey Cathepsin K. Bone 1999, 25, 205-209.
31. Kumar, S.; Dare, L.; Vasko-Moser, J. A.; James, I. E.; Blake, S. M.; Rickard, D. J.; Hwang, S.-M.; Tomaszek, T.; Yamashita, D. S.; Marquis, R. W.; Oh, H.; Jeong, J. U.; Veber, D. F.; Gowen, M.; Lark, M. W.; Stroup, G. A Highly Potent Inhibitor of Cathepin K (Relacatib) Reduces Biomarkers of Bone Resorption Both in Vitro and in an Acute Model of Elevated Bone Turnover in Vivo in Monkeys. Bone 2007, 40, 122-131.
32. Stoch, S. A.; Wagner, J. A. Cathepsin K Inhibitors: A Novel Target for Osteoporosis Therapy. Clin. Pharmacol. Ther. 2008, 83, 172-176.