Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K

…, RV Mendonca, E Springman, J McCarter…

Index: Palmer, James T.; Bryant, Clifford; Wang, Dan-Xiong; Davis, Dana E.; Setti, Eduardo L.; Rydzewski, Robert M.; Venkatraman, Shankar; Tian, Zong-Qiang; Burrill, Leland C.; Mendonca, Rohan V.; Springman, Eric; McCarter, John; Chung, Tobee; Cheung, Harry; Janc, James W.; McGrath, Mary; Somoza, John R.; Enriquez, Philip; Yu, Z. Walter; Strickley, Robert M.; Liu, Liang; Venuti, Michael C.; Percival, M. David; Falgueyret, Jean-Pierre; Prasit, Peppi; Oballa, Renata; Riendeau, Denis; Young, Robert N.; Wesolowski, Gregg; Rodan, Sevgi B.; Johnson, Colena; Kimmel, Donald B.; Rodan, Gideon Journal of Medicinal Chemistry, 2005 , vol. 48, # 24 p. 7520 - 7534

Full Text: HTML

Citation Number: 91

Abstract

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 ( ...