We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.

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Enzyme inhibiting activityEnzyme inhibiting activity X 0220 3,4-Disubstituted Azetidinones as Selective Inhibitors of the Cysteine Protease Cathepsin K. Exploring P2 Elements for Selectivity. -A series of 3,4-disubstituted azetidinones of type (I) is tested as inhibitors of the cysteine protease cathepsin K (Cat K). (Ia) is a potent and non-selective inhibitor of Cat K. (Ib) is the most selective inhibitor. -(SETTI*, E. L.; DAVIS, D.; CHUNG, T.; MCCARTER, J.; Bioorg. Med.