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1.
Bioorg Med Chem Lett ; 18(3): 923-8, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18226527

ABSTRACT

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.


Subject(s)
Biphenyl Compounds/pharmacology , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Animals , Azepines/chemistry , Azepines/pharmacology , Cathepsin K , Collagen/drug effects , Collagen/immunology , Dogs , Fibroblasts/drug effects , Humans , Models, Biological , Molecular Structure , Osteoporosis, Postmenopausal/drug therapy , Skin/cytology , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology
2.
J Med Chem ; 48(24): 7520-34, 2005 Dec 01.
Article in English | MEDLINE | ID: mdl-16302794

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.


Subject(s)
Benzamides/chemical synthesis , Bone Density Conservation Agents/chemical synthesis , Cathepsins/antagonists & inhibitors , Nitriles/chemical synthesis , Thiazoles/chemical synthesis , 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
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