Discovery of <i>N</i>‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2<i>S</i>,5<i>R</i>)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2<i>H</i>‑tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis

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.基质金属蛋白酶-13（Matrix metalloproteinase-13，MMP-13）是一类锌依赖性蛋白酶，负责剪切Ⅱ型胶原蛋白——关节软骨的主要结构蛋白。该软骨基质的降解会引发骨关节炎的发生发展。我们此前曾报道过一类强效且高选择性的含羧酸基团的MMP-13抑制剂，但此类化合物在临床前毒理学受试动物中表现出的肾毒性阻碍了其开发进程。研究推测，人类有机阴离子转运体3（human organic anion transporter 3，hOAT3）介导的化合物在肾脏内蓄积，是导致该肾毒性发现的潜在诱因。本文报道了我们针对非羧酸类先导化合物的优化工作，以提升其MMP-13抑制活性与药代动力学特性，最终成功获得化合物43a：在相当的药物暴露量下，该化合物未出现此前观察到的临床前毒副作用。