β-Substituted Cyclohexanecarboxamide:  A Nonpeptidic Framework for the Design of Potent Inhibitors of Cathepsin K

A new series of nonpeptidic cathepsin K inhibitors that are based on a β-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block met...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-02, Vol.49 (3), p.1066-1079
Main Authors: Crane, Sheldon N, Black, W. Cameron, Palmer, James T, Davis, Dana E, Setti, Eduardo, Robichaud, Joel, Paquet, Julie, Oballa, Renata M, Bayly, Christopher I, McKay, Daniel J, Somoza, John R, Chauret, Natalie, Seto, Carmai, Scheigetz, John, Wesolowski, Greg, Massé, Frederic, Desmarais, Sylvie, Ouellet, Marc
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Aminoacetonitrile - analogs & derivatives
Aminoacetonitrile - chemical synthesis
Aminoacetonitrile - chemistry
Aminoacetonitrile - pharmacology
Animals
Biological and medical sciences
Biological Availability
Bones, joints and connective tissue. Antiinflammatory agents
Cathepsin K
Cathepsins - antagonists & inhibitors
Cathepsins - chemistry
Crystallography, X-Ray
Cyclohexanes - chemical synthesis
Cyclohexanes - chemistry
Cyclohexanes - pharmacology
Dogs
Half-Life
Male
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship
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Summary:A new series of nonpeptidic cathepsin K inhibitors that are based on a β-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (−)-34a (hrab Cat K IC50 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs:  F 55%, t 1/2 = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm051059p