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

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 ( 1100-fold selectivity vs Cat B, L, S, C, H, Z, and V, 110-fold vs Cat F)...