Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis.

Journal Article (Journal Article)

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 IC 50 = 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.

Full Text

Duke Authors

Cited Authors

  • Robichaud, J; Black, WC; Thérien, M; Paquet, J; Oballa, RM; Bayly, CI; McKay, DJ; Wang, Q; Isabel, E; Léger, S; Mellon, C; Kimmel, DB; Wesolowski, G; Percival, MD; Massé, F; Desmarais, S; Falgueyret, J-P; Crane, SN

Published Date

  • October 2008

Published In

Volume / Issue

  • 51 / 20

Start / End Page

  • 6410 - 6420

PubMed ID

  • 18811135

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm800610j


  • eng