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Design of potent, selective, and orally bioavailable inhibitors of cysteine protease cathepsin k.

Abstract：

:Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Tavares FX,Boncek V,Deaton DN,Hassell AM,Long ST,Miller AB,Payne AA,Miller LR,Shewchuk LM,Wells-Knecht K,Willard DH Jr,Wright LL,Zhou HQ

doi

10.1021/jm030373l

keywords:

subject

Has Abstract

pub_date

2004-01-29 00:00:00

pages

588-99

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

47

pub_type

杂志文章

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