| Abstract
| - A new series of nonpeptidic cathepsin K inhibitors that are based on a β-substituted cyclohexanecarboxamidemotif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptionalselectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexylring led to compounds with excellent pharmacokinetic properties. Considering the well-established role ofcathepsin 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%, t1/2 = 15 h) exhibit great potential fordevelopment as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
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