Identification of a Nonbasic, Nitrile-Containing Cathepsin K Inhibitor (MK-1256) that is Efficacious in a Monkey Model of Osteoporosis.
作者
Robichaud, Joel;Black, W. Cameron;Therien, Michel;Paquet, Julie;Oballa, Renata M.;Bayly, Christopher I.;McKay, Daniel J.;Wang, Qingping;Isabel, Elise;Leger, Serge;Mellon, Christophe;Kimmel, Donald B.;Wesolowski, Gregg;Percival, M. David;Masse, Frederic;De
[摘要]：Herein, the authors report on the identification of nonbasic, potent, and highly selective, nitrile-contg. cathepsin K (Cat K) inhibitors that are built on the previously identified cyclohexanecarboxamide core structure. Subsequent to the initial investigations, the authors have found that incorporation of five-membered heterocycles as P2-P3 linkers allowed for the introduction of a Me sulfone P3-substituent that was not tolerated in inhibitors contg. a six-membered arom. P2-P3 linker. The combination of a five-membered N-methylpyrazole linker and a Me sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in the 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 MK-1256 (I), 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.
