ABSTRACT
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Subject(s)
Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Picolinic Acids/chemistry , Protease Inhibitors/chemistry , Tetrazoles/chemistry , Administration, Oral , Animals , Binding Sites , Cartilage/drug effects , Cartilage/metabolism , Catalytic Domain , Crystallography, X-Ray , Disease Models, Animal , Drug Discovery , Matrix Metalloproteinase 13/metabolism , Picolinic Acids/chemical synthesis , Picolinic Acids/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Rats , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Zinc/chemistryABSTRACT
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.