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

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

Affiliation

  • 1 Celera Genomics, Inc., 180 Kimball Way, South San Francisco, California 94080, USA. jim.palmer@celera.com
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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