Recent Research Advances in Selective Matrix Metalloproteinase-13 Inhibitors as Anti-Osteoarthritis Agents.

Matrix metalloproteinase-13 (MMP-13) plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). The subtle differences between the S1' loop of MMP-13 and that of other MMPs offer a structural base for the design of selective MMP-13 inhibitors to mitigate the unperceived risk associated with inhibiting other MMP isoforms. In this review, we summarize zinc-binding and non-zinc-binding selective MMP-13 inhibitors. The zinc-binding MMP-13 inhibitors contain a small set of zinc-binding groups (ZBGs), including hydroxamic acid, pyrimidinetrione, reversed hydroxamic acid and hydantoin, carboxylic acid, 1,2,4,-triazole, and 1,2,4,-triazolone. The non-zinc-binding MMP-13 inhibitors have different structural scaffolds, including diphenyl ethers, biaryls (aryltetrazoliums, arylfurans, pyrazole-indoles), pyrimidines, and aryl/cycloalkyl-fused pyrimidines. This review provides a systematic overview of recent developments in MMP-13 inhibitors for the treatment of OA, with emphasis on their enzyme inhibitory potency, selectivity, and biological activities, and highlights the various binding modes of typical inhibitors with MMP-13.