Matrix metalloproteinase-13 selective inhibitors.

Matrix metalloproteinase-13 (MMP13) is the primary protease responsible for the irreversible degradation of type II collagen in the extracellular matrix (ECM), playing a pivotal role in the pathogenesis of osteoarthritis (OA), rheumatoid arthritis (RA), and various malignant cancers. While early clinical efforts with broad-spectrum zinc-chelating inhibitors were abandoned due to dose-limiting musculoskeletal syndrome (MSS), recent research has focused on achieving high isoform selectivity by targeting unique structural features such as the deep S1' specificity pocket and the MMP13-specific S1'' side pocket. This chapter reviews a wide set of advanced inhibitor scaffolds, including selective sulfonamide hydroxamates, hydantoins such as AZD6605, and non-zinc-binding templates like quinazoline-2-carboxamides and pyrimidine-dicarboxamides. Furthermore, we discuss innovative strategies such as the use of allosteric inhibitors, exosite-binding agents targeting the hemopexin domain, and selectively deuterated molecules (e.g., AQU-019) to improve metabolic stability. Finally, the chapter highlights the clinical potential of neutralizing antibodies (e.g., 14D10), targeted polypharmacology for dual MMP10/13 inhibition, and the development of selective PET radiotracers for non-invasive monitoring of disease progression and atherosclerotic plaque instability.