Download MendeleyBeta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K.
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.(2006) J Med Chem 49: 1066-1079
- PubMed: 16451072
- DOI: https://doi.org/10.1021/jm051059p
- Primary Citation of Related Structures:
2F7D - PubMed Abstract:
A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-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 IC(50) 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.
Organizational Affiliation:
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Quebec, Canada, H9H 3L1. sheldon_crane@merck.com
