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.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Biological Availability
  • Biomarkers / urine
  • Bone Density Conservation Agents / chemical synthesis*
  • Bone Density Conservation Agents / chemistry
  • Bone Density Conservation Agents / pharmacology
  • Bone Resorption / urine
  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Cathepsins / chemistry
  • Cattle
  • Collagen / antagonists & inhibitors
  • Collagen / metabolism
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Kinetics
  • Macaca mulatta
  • Models, Molecular
  • Molecular Structure
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Nitriles / pharmacology
  • Rabbits
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • Benzamides
  • Biomarkers
  • Bone Density Conservation Agents
  • CRA 013783
  • Nitriles
  • Thiazoles
  • Collagen
  • Cathepsins
  • CTSK protein, human
  • Cathepsin K
  • Ctsk protein, rat