Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

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 S1′ 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.

Graphical abstractPotent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified which inhibit production of type II collagen neoepitope (TIINE), a biomarker of cartilage degradation, and afforded cartilage protection in a preclinical rat osteoarthritis model.Figure optionsDownload full-size imageDownload as PowerPoint slide