ABSTRACT
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.
Subject(s)
Matrix Metalloproteinase 13/drug effects , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/pharmacology , Osteoarthritis/drug therapy , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Animals , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Collagenases/drug effects , Dogs , Drug Design , Humans , Kidney/metabolism , Macaca fascicularis , Male , Matrix Metalloproteinase Inhibitors/toxicity , Models, Molecular , Organic Anion Transporters, Sodium-Independent/metabolism , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.
Subject(s)
Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Benzoxazoles/chemical synthesis , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Intramolecular Oxidoreductases/chemistry , Intramolecular Oxidoreductases/metabolism , Models, Molecular , Molecular Conformation , Prostaglandin-E Synthases , Structure-Activity RelationshipABSTRACT
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.
