Subject(s)
Antirheumatic Agents/pharmacology , Drug Design , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Agammaglobulinaemia Tyrosine Kinase , Amino Acid Sequence , Animals , Antirheumatic Agents/chemistry , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/enzymology , Binding Sites , Disease Models, Animal , Molecular Sequence Data , Oligopeptides/chemistry , Oligopeptides/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/metabolism , Rodentia , Structure-Activity RelationshipABSTRACT
Using a scaleable, directed library approach based on orthogonally protected advanced intermediates, we have prepared a series of potent keto-1,2,4-oxadiazoles designed to explore the P(2) binding pocket of human mast cell tryptase, while building in a high degree of selectivity over human trypsin and other serine proteases.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Mast Cells/drug effects , Oxadiazoles/chemical synthesis , Serine Endopeptidases/drug effects , Animals , Binding Sites/drug effects , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Humans , Mast Cells/enzymology , Mice , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Stereoisomerism , Structure-Activity Relationship , TryptasesABSTRACT
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/pharmacologyABSTRACT
Cathepsin K is highly expressed in human osteoclasts, and is implicated in bone resorption. This makes it an attractive target for the treatment of osteoporosis. Peptides containing 2-amino-1'-hydroxymethyl ketones and 2-amino-1'-alkoxymethyl ketones were discovered as potent inhibitors of cathepsin K. A novel synthetic route was devised to facilitate rapid elucidation of the SAR of these inhibitors. The synthesis and SAR of hydroxymethyl ketones are presented.
