(1 R,2 R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3- b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A potent and highly selective cathepsin k inhibitor for the treatment of osteoarthritis

Journal of Medicinal Chemistry

Volumn 55, Issue 14, 2012, Pages 6363-6374

  Dossetter, Alexander G ^a   Beeley, Howard ^a   Bowyer, Jonathan ^a   Cook, Calum R ^a   Crawford, James J ^a   Finlayson, Jonathan E ^a   Heron, Nicola M ^a   Heyes, Christine ^a   Highton, Adrian J ^a   Hudson, Julian A ^a   Jestel, Anja ^b   Kenny, Peter W ^a   Krapp, Stephan ^b   Martin, Scott ^a   MacFaul, Philip A ^a   McGuire, Thomas M ^a   Gutierrez, Pablo Morentin ^a   Morley, Andrew D ^a   Morris, Jeffrey J ^a   Page, Ken M ^a   Ribeiro, Lyn Rosenbrier ^a   Sawney, Helen ^a   Steinbacher, Stefan ^b   Smith, Caroline ^a   Vickers, Madeleine ^a   more..

^a ASTRAZENECA   (United Kingdom)

^b PROTEROS BIOSTRUCTURES GMBH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AZD 4996; CATHEPSIN K INHIBITOR; N (1 CYANOCYCLOPROPYL) 2 (6 METHOXY 1,3,4,5 TETRAHYDROPYRIDO[4,3 B]INDOLE 2 CARBONYL)CYCLOHEXANECARBOXAMIDE; UNCLASSIFIED DRUG; CARBOLINE DERIVATIVE; CATHEPSIN K; INDOLE DERIVATIVE; N (1 CYANOCYCLOPROPYL) 2 (6 METHOXY 1,3,4,5 TETRAHYDROPYRIDO(4,3 B)INDOLE 2 CARBONYL)CYCLOHEXANECARBOXAMIDE; N-(1-CYANOCYCLOPROPYL)-2-(6-METHOXY-1,3,4,5-TETRAHYDROPYRIDO(4,3-B)INDOLE-2-CARBONYL)CYCLOHEXANECARBOXAMIDE; PROTEINASE INHIBITOR;

ANIMAL EXPERIMENT; ARTICLE; DRUG POTENCY; DRUG SELECTIVITY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; IC 50; LIPOPHILICITY; MALE; NONHUMAN; OSTEOARTHRITIS; RAT; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DOG; DRUG ANTAGONISM; ENZYME SPECIFICITY; ENZYMOLOGY; METABOLISM; PROTEIN CONFORMATION;

ANIMALS; CARBOLINES; CATHEPSIN K; DOGS; HUMANS; INDOLES; INHIBITORY CONCENTRATION 50; MALE; MODELS, MOLECULAR; OSTEOARTHRITIS; PROTEASE INHIBITORS; PROTEIN CONFORMATION; RATS; SUBSTRATE SPECIFICITY;

EID: 84864250242     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm3007257     Document Type: Article

References (47)

1. Hunter, D. J.; Felson, D. T. Osteoarthritis BMJ [Br. Med. J.] 2006, 332, 639-642
2. Lawrence, R. C.; Felson, D. T.; Helmick, C. G.; Arnold, L. M.; Choi, H.; Deyo, R. A.; Gabriel, S.; Hirsch, R.; Hochberg, M. C.; Hunder, G. G.; Jordan, J. M.; Katz, J. N.; Kremers, H. M.; Wolfe, F. National Arthritis Data Workgroup Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II Arthritis Rheum. 2008, 58, 26-35
3. WHO Disease and Injury country estimates http://www.who.int/healthinfo/ global-burden-disease/estimates-country/en/index.html.
4. Felson, D. T.; Chaisson, C. E.; Hill, C. L.; Totterman, S. M.; Gale, M. E.; Skinner, K. M.; Kazis, L.; Gale, D. R. The association of bone marrow lesions with pain in knee osteoarthritis Ann. Intern. Med. 2001, 134, 541-549
5. Alzahrani, K.; Gandhi, R.; Debeer, J.; Petruccelli, D.; Mahomed, N. Prevalence of clinically significant improvement following total knee replacement J. Rheumatol. 2011, 38, 753-759
6. Teitelbaum, S. L. Bone resorption by osteoclasts Science (Washington, D. C.) 2000, 289, 1504-1508
7. Gowen, M.; Lazner, F.; Dodds, R.; Kapadia, R.; Feild, 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. 1999, 14, 1654-1663
8. Gupta, S.; Singh, R. K.; Dastidar, S.; Ray, A. Cysteine cathepsin S as an immunomodulatory target: present and future trends Expert Opin. Ther. Targets 2008, 12, 291-299
9. Stoch, S. A.; Wagner, J. A. Cathepsin K inhibitors: a novel target for osteoporosis therapy Clin. Pharmacol. Ther. 2008, 83, 172-176
10. Yasuda, Y.; Kaleta, J.; Broemme, D. The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics Adv. Drug Delivery Rev. 2005, 57, 973-993
11. Yang, M.; Sun, J.; Zhang, T.; Liu, J.; Zhang, J.; Shi, M. A.; Darakhshan, F.; Guerre-Millo, M.; Clement, K.; Gelb, B. D.; Dolgnov, G.; Shi, G. Deficiency and Inhibition of Cathepsin K Reduce Body Weight Gain and Increase Glucose Metabolism in Mice Arterioscler., Thromb., Vasc. Biol. 2008, 28, 2202-2208
12. Vasiljeva, O.; Reinheckel, T.; Peters, C.; Turk, D.; Turk, V.; Turk, B. Emerging roles of cysteine cathepsins in disease and their potential as drug targets Curr. Pharm. Des. 2007, 13, 387-403
13. Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L. T.; Falgueyret, J.; Kimmel, D. B.; Lamontagne, S.; Leger, S.; LeRiche, T.; Li, C. S.; Masse, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.; Truong, V.; Venuti, M. C.; 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
14. Stoch, S. A.; Zajic, S.; Stone, J.; Miller, D. L.; Van, D., K.; Gutierrez, M. J.; De, D., M.; Liu, L.; Liu, Q.; Scott, B. B.; Panebianco, D.; Jin, B.; Duong, L. T.; Gottesdiener, K.; Wagner, J. A. Effect of the Cathepsin K Inhibitor Odanacatib on Bone Resorption Biomarkers in Healthy Postmenopausal Women: Two Double-Blind, Randomized, Placebo-Controlled Phase I Studies Clin. Pharmacol. Ther. (N. Y., NY, U. S.) 2009, 86, 175-182
15. Eisman, J. A.; Bone, H. G.; Hosking, D. J.; McClung, M. R.; Reid, I. R.; Rizzoli, R.; Resch, H.; Verbruggen, N.; Hustad, C. M.; Da, S. C.; Petrovic, R.; Santora, A. C.; Ince, B. A.; Lombardi, A. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect J. Bone Miner. Res. 2011, 26, 242-251
16. Yamashita, D. S.; Marquis, R. W.; Xie, R.; Nidamarthy, S. D.; Oh, H.; Jeong, J. U.; Erhard, K. F.; Ward, K. W.; Roethke, T. J.; Smith, B. R.; Cheng, H.; Geng, X.; Lin, F.; Offen, P. H.; Wang, B.; Nevins, N.; Head, M. S.; Haltiwanger, R. C.; Narducci, S.; Amy, A.; Liable-Sands, L. M.; Zhao, B.; Smith, W. W.; Janson, C. A.; Gao, E.; Tomaszek, T.; McQueney, M.; James, I. E.; Gress, C. J.; Zembryki, D. L.; Lark, M. W.; Veber, D. F. Structure-Activity Relationships of 5-, 6-, and 7-Methyl-Substituted Azepan-3-one Cathepsin K Inhibitors J. Med. Chem. 2006, 49, 1597-1612
17. Kumar, S.; Dare, L.; Vasko-Moser, J. A.; James, I. E.; Blake, S. M.; Rickard, D. J.; Hwang, S.; 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 cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys Bone (San Diego, CA, U. S.) 2007, 40, 122-131
18. Bailey, A.; Pairaudeau, G.; Patel, A.; Thom, S. WO2004000825A1, 2003.
19. Black, W. C.; Percival, M. D. The consequences of lysosomotropism on the design of selective cathepsin K inhibitors ChemBioChem 2006, 7, 1525-1535
20. Falgueyret, J.; Desmarais, S.; Oballa, R.; Black, W. C.; Cromlish, W.; Khougaz, K.; Lamontagne, S.; Masse, F.; Riendeau, D.; Toulmond, S.; Percival, M. D. Lysosomotropism of Basic Cathepsin K Inhibitors Contributes to Increased Cellular Potencies against Off-Target Cathepsins and Reduced Functional Selectivity J. Med. Chem. 2005, 48, 7535-7543
21. Hann, M. M.; Leach, A. R.; Harper, G. Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery J. Chem. Inf. Comput. Sci. 2001, 41, 856-864
22. 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
23. Robichaud, J.; Bayly, C. I.; Black, W. C.; Desmarais, S.; Leger, S.; Masse, F.; McKay, D. J.; Oballa, R. M.; Paquet, J.; Percival, M. D.; Truchon, J.; 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
24. Berkessel, A.; Glaubitz, K.; Lex, J. Enantiomerically pure β-amino acids: a convenient access to both enantiomers of trans-2- aminocyclohexanecarboxylic acid Eur. J. Org. Chem. 2002, 2948-2952
25. Harbert, C. A.; Plattner, J. J.; Welch, W. M.; Weissman, A.; Koe, B. K. Neuroleptic activity in 5-aryltetrahydro-γ-carbolines J. Med. Chem. 1980, 23, 635-643
26. Ram, S.; Spicer, L. D. Debenzylation of N-benzylamino derivatives by catalytic transfer hydrogenation with ammonium formate Synth. Commun. 1987, 17, 415-418
27. Waring, M. J. Lipophilicity in drug discovery Expert Opin. Drug Discovery 2010, 5, 235-248
28. Andersson, S.; Armstrong, A.; Bjoere, A.; Bowker, S.; Chapman, S.; Davies, R.; Donald, C.; Egner, B.; Elebring, T.; Holmqvist, S.; Inghardt, T.; Johannesson, P.; Johansson, M.; Johnstone, C.; Kemmitt, P.; Kihlberg, J.; Korsgren, P.; Lemurell, M.; Moore, J.; Pettersson, J. A.; Pointon, H.; Ponten, F.; Schofield, P.; Selmi, N.; Whittamore, P. Making medicinal chemistry more effective-application of Lean Sigma to improve processes, speed and quality Drug Discovery Today 2009, 14, 598-604
29. Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T. The design of leadlike combinatorial libraries Angew. Chem., Int. Ed. 1999, 38, 3743-3748
30. Oprea, T. I.; Davis, A. M.; Teague, S. J.; Leeson, P. D. Is There a Difference between Leads and Drugs? A Historical Perspective J. Chem. Inf. Comput. Sci. 2001, 41, 1308-1315
31. Williams, J. W.; Morrison, J. F. The kinetics of reversible tight-binding inhibition Methods Enzymol. 1979, 63, 437-467
32. Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.; Gauthier, J. Y.; Kimmel, D. B.; Leger, S.; Masse, F.; McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Therien, M.; Truong, V.; 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
33. Johnson, T. W.; Dress, K. R.; Edwards, M. Using the Golden Triangle to optimize clearance and oral absorption Bioorg. Med. Chem. Lett. 2009, 19, 5560-5564
34. Leach, A. G.; Jones, H. D.; Cosgrove, D. A.; Kenny, P. W.; Ruston, L.; MacFaul, P.; Wood, J. M.; Colclough, N.; Law, B. Matched Molecular Pairs as a Guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure J. Med. Chem. 2006, 49, 6672-6682
35. Dossetter, A. G. A statistical analysis of in vitro human microsomal metabolic stability of small phenyl group substituents, leading to improved design sets for parallel SAR exploration of a chemical series Bioorg. Med. Chem. 2010, 18, 4405-4414
36. Lewis, M. L.; Cucurull-Sanchez, L. Structural pairwise comparisons of HLM stability of phenyl derivatives: Introduction of the Pfizer metabolism index (PMI) and metabolism-lipophilicity efficiency (MLE) J. Comput.-Aided Mol. Des. 2009, 23, 97-103
37. Henderson, J. D.; Olson, R. D.; Ravis, W. R. Pharmacokinetic calculator program for generation of initial parameter estimates from a three-compartment infusion model J. Pharmacol. Methods 1985, 14, 13-24
38. McGinnity, D. F.; Collington, J; Austin, R. P.; Riley, R. J. Evaluation of Human Pharmacokinetics, Therapeutic Dose and Exposure Predictions Using Marketed Oral Drugs Curr. Drug Metab. 2007, 8, 463-479
39. Sadick, M.; Attenberger, U.; Kraenzlin, B.; Kayed, H.; Schoenberg, S. O.; Gretz, N.; Schock-Kusch, D. Two non-invasive GFR-estimation methods in rat models of polycystic kidney disease: 3.0 T dynamic contrast-enhanced MRI and optical imaging Nephrol., Dial., Transplant. 2011, 26, 3101-3108
40. Rowland, M.; Tozer, T. N. In Clinical Pharmacokinetics; Concepts and Application; 3 rd ed., Chapter 11, p 171.
41. Kuhn, B.; Mohr, P.; Stahl, M. Intramolecular Hydrogen Bonding in Medicinal Chemistry J. Med. Chem. 2010, 53, 2601-2611
42. Ashwood, V. A.; Field, M. J.; Horwell, D. C.; Julien-Larose, C.; Lewthwaite, R. A.; McCleary, S.; Pritchard, M. C.; Raphy, J.; Singh, L. Utilization of an Intramolecular Hydrogen Bond To Increase the CNS Penetration of an NK1 Receptor Antagonist J. Med. Chem. 2001, 44, 2276-2285
43. Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.; Suzuki, N.; Furuya, S.; Fujino, M. Discovery of a Thieno[2,3- d ]pyrimidine-2,4-dione Bearing a p -Methoxyureidophenyl Moiety at the 6-Position: A Highly Potent and Orally Bioavailable Nonpeptide Antagonist for the Human Luteinizing Hormone-Releasing Hormone Receptor J. Med. Chem. 2003, 46, 113-124
44. Rezai, T.; Bock, J. E.; Zhou, M. V.; Kalyanaraman, C.; Lokey, R. S.; Jacobson, M. P. Conformational Flexibility, Internal Hydrogen Bonding, and Passive Membrane Permeability: Successful in Silico Prediction of the Relative Permeabilities of Cyclic Peptides J. Am. Chem. Soc. 2006, 128, 14073-14080
45. Garnero, P.; Ferreras, M.; Karsdal, M.; Nicamhlaoibh, R.; Risteli, J.; Borel, O.; Qvist, P.; Delmas, P. D.; Foged, N. T.; Delaisse, J. M. The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation J. Bone Miner. Res. 2003, 18, 859-867
46. Herrmann, M.; Seibel, M. The amino- and carboxyterminal cross-linked telopeptides of collagen type I, NTX-I and CTX-I: A comparative review Clin. Chim. Acta 2008, 393, 57-75
47. Okuno, S.; Inaba, M.; Kitatani, K.; Ishimura, E.; Yamakawa, T.; Nishizawa, Y. Serum levels of C-terminal telopeptide of type I collagen: A useful new marker of cortical bone loss in hemodialysis patients Osteoporosis Int. 2005, 16, 501-509