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Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2005 Dec 01; Vol. 48 (24), pp. 7520-34. - Publication Year :
- 2005
-
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.
- Subjects :
- Administration, Oral
Animals
Benzamides chemistry
Benzamides pharmacology
Biological Availability
Biomarkers urine
Bone Density Conservation Agents chemistry
Bone Density Conservation Agents pharmacology
Bone Resorption urine
Cathepsin K
Cathepsins chemistry
Cattle
Collagen antagonists & inhibitors
Collagen metabolism
Crystallography, X-Ray
Drug Design
Humans
Kinetics
Macaca mulatta
Models, Molecular
Molecular Structure
Nitriles chemistry
Nitriles pharmacology
Rabbits
Rats
Structure-Activity Relationship
Thiazoles chemistry
Thiazoles pharmacology
Benzamides chemical synthesis
Bone Density Conservation Agents chemical synthesis
Cathepsins antagonists & inhibitors
Nitriles chemical synthesis
Thiazoles chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 48
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16302794
- Full Text :
- https://doi.org/10.1021/jm058198r