Design and Synthesis of Tri-Ring P3 Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K
journal contributionposted on 2005-12-01, 00:00 authored by James T. Palmer, Clifford Bryant, Dan-Xiong Wang, Dana E. Davis, Eduardo L. Setti, Robert M. Rydzewski, Shankar Venkatraman, Zong-Qiang Tian, Leland C. Burrill, Rohan V. Mendonca, Eric Springman, John McCarter, Tobee Chung, Harry Cheung, James W. Janc, Mary McGrath, John R. Somoza, Philip Enriquez, Z. Walter Yu, Robert M. Strickley, Liang Liu, Michael C. Venuti, M. David Percival, Jean-Pierre Falgueyret, Peppi Prasit, Renata Oballa, Denis Riendeau, Robert N. Young, Gregg Wesolowski, Sevgi B. Rodan, Colena Johnson, Donald B. Kimmel, Gideon Rodan
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.