Jiangsu Key Laboratory for TCM Formulae Research, Nanjing University of Chinese Medicine, 138 Xianlin Road, 210046, Nanjing, Jiangsu, P.R. China.
Curr Med Chem. 2011;18(7):977-1001. doi: 10.2174/092986711794940905.
Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage-specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose- and duration-dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure-activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13.
骨关节炎（OA）是中老年人关节疼痛和残疾的主要原因，其特征是关节软骨进行性丧失，最终导致一个涉及软骨基质各种成分降解的复杂过程，其中主要的是软骨特异性 II 型胶原（CII）和聚集蛋白聚糖。虽然聚集蛋白聚糖的丢失被认为是一个早期和可逆的过程，但 CII 的降解被认为是不可逆的，是软骨结构和功能完整性丧失的关键步骤。在各种基质金属蛋白酶（MMPs）中，MMP-13 特异性表达于 OA 患者的软骨中，而在正常成人软骨中不存在。它是 OA 软骨中的主要胶原酶，对 CII 的活性最高。然而，为治疗 OA 而开发的广谱 MMP 抑制剂的临床应用受到了人类剂量和时间依赖性肌肉骨骼副作用的限制。因此，选择性抑制 MMP-13 似乎是一个有吸引力的治疗目标。本文主要综述了 90 年代末以来针对 OA 的选择性 MMP-13 抑制剂的开发情况，包括含有特定锌结合基团的低分子量合成化合物和非锌结合基团。此外，还对 MMP-13 和聚集蛋白聚糖双重抑制剂进行了综述。特别强调了在这一领域中针对先导化合物搜索的逻辑问题以及结构-活性关系（SAR）。通过这些方法，通过选择性抑制 MMP-13 治疗 OA 出现了新的希望。
