Design and synthesis of tri-ring P-3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K
Palmer, JT; Bryant, C; Wang, DX; Davis, DE; Setti, EL; Rydzewski, RM; Venkatraman, S; Tian, ZQ; Burrill, LC; Mendonca, RV; Springman, E; McCarter, J; Chung, T; Cheung, H; Janc, JW; McGrath, M; Somoza, JR; Enriquez, P; Yu, ZW; Strickley, RM; Liu, L; Venuti, MC; Percival, MD; Falgueyret, JP; Prasit, P; Oballa, R; Riendeau, D; Young, RN; Wesolowski, G; Rodan, SB; Johnson, C; Kimmel, DB; Rodan, G
We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P-2. 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.