鉴定新型、外切酶结合基质金属蛋白酶-13 抑制剂支架。
Identification of novel, exosite-binding matrix metalloproteinase-13 inhibitor scaffolds.
机构信息
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, United States.
出版信息
Bioorg Med Chem Lett. 2011 Dec 1;21(23):7180-4. doi: 10.1016/j.bmcl.2011.09.077. Epub 2011 Sep 22.
Abstract
Matrix metalloproteinase-13 (MMP-13) has been implicated as the protease responsible for collagen degradation in cartilage during osteoarthritis (OA). Compounds that inhibit the metalloproteinase at the Zn binding site typically lack specificity among MMP family members. Analogs of the low-micromolar lead MMP-13 inhibitor 4, discovered through high-throughput screening, were synthesized to investigate structure-activity relationships in this inhibitor series. Systematic modifications of 4 led to the discovery of MMP-13 inhibitors 20 and 24 which are more selective than 4 against other MMPs. Compound 20 is also approximately fivefold more potent as an MMP-13 inhibitor than the original HTS-derived lead compound 4.
摘要
基质金属蛋白酶-13（MMP-13）已被认为是骨关节炎（OA）中负责软骨胶原降解的蛋白酶。在 Zn 结合部位抑制金属蛋白酶的化合物通常缺乏 MMP 家族成员之间的特异性。通过高通量筛选发现的低微摩尔级先导 MMP-13 抑制剂 4 的类似物被合成，以研究该抑制剂系列中的构效关系。对 4 的系统修饰导致发现了 MMP-13 抑制剂 20 和 24，它们比 4 对其他 MMP 更具选择性。化合物 20 作为 MMP-13 抑制剂的效力也比原始高通量筛选衍生的先导化合物 4 约高出五倍。
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