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

  • J Med Chem. 2005 Dec 1;48(24):7520-34. doi: 10.1021/jm058198r.
James T Palmer  1 ,  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
Affiliations
  • 1. Celera Genomics, Inc., 180 Kimball Way, South San Francisco, California 94080, USA. [email protected]
PMID: 16302794 DOI: 10.1021/jm058198r
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 (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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