Identification of a Nonbasic, Nitrile-Containing Cathepsin K Inhibitor (MK-1256) that is Efficacious in a Monkey Model of Osteoporosis

详细信息    查看全文

• 作者：Jö ; el Robichaud ; W. Cameron Black ; Michel Thé ; rien ; Julie Paquet ; Renata M. Oballa ; Christopher I. Bayly ; Daniel J. McKay ; Qingping Wang ; Elise Isabel ; Serge Lé ; ger ; Christophe Mellon
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 23, 2008
• 年：2008
• 卷：51
• 期：20
• 页码：6410-6420
• 全文大小：249K
• 年卷期：v.51,no.20(October 23, 2008)
• ISSN：1520-4804

文摘

Herein, we report on the identification of nonbasic, potent, and highly selective, nitrile-containing cathepsin K (Cat K) inhibitors that are built on our previously identified cyclohexanecarboxamide core structure. Subsequent to our initial investigations, we have found that incorporation of five-membered heterocycles as P2−P3 linkers allowed for the introduction of a methyl sulfone P3-substitutent that was not tolerated in inhibitors containing a six-membered aromatic P2−P3 linker. The combination of a five-membered N-methylpyrazole linker and a methyl sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in our functional bone resorption assay. Issues that arose because of metabolic demethylation of the N-methylpyrazole were addressed through introduction of a 2,2,2-trifluoroethyl substituent. This culminated in the identification of 31 (MK-1256), a potent (Cat K IC₅₀ = 0.62 nM) and selective (>1100-fold selectivity vs Cat B, L, S, C, H, Z, and V, 110-fold vs Cat F) inhibitor of cathepsin K that is efficacious in a monkey model of osteoporosis.