Design and synthesis of tri-ring P-3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K

• Published in: Journal of medicinal chemistry Vol. 48; no. 24; pp. 7520 - 7534
• Main Authors: 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, 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 01.12.2005
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; KETONES; ENZYME; OSTEOCLASTS; GENE; NITRILES; PYCNODYSOSTOSIS; IDENTIFICATION; OSTEOPETROSIS; EXPRESSION; BONE-RESORPTION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm058198r

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.