2F7D

A mutant rabbit cathepsin K with a nitrile inhibitor

2F7D の概要

• エントリーDOI: 10.2210/pdb2f7d/pdb
• 分子名称: Cathepsin K, (1R,2R)-N-(2-AMINOETHYL)-2-{[(4-METHOXYPHENYL)SULFONYL]METHYL}CYCLOHEXANECARBOXAMIDE (3 entities in total)
• 機能のキーワード: papain cysteine protease, hydrolase
• 由来する生物種: Oryctolagus cuniculus (rabbit)
• 細胞内の位置: Lysosome : P43236
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23908.96

構造登録者

Somoza, J.R. (登録日: 2005-11-30, 公開日: 2006-03-07, 最終更新日: 2024-11-06)

主引用文献

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.
Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K.
J.Med.Chem., 49:1066-1079, 2006

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.

PubMed: 16451072
DOI: 10.1021/jm051059p

実験手法

X-RAY DIFFRACTION (1.9 Å)