开发一种假定的 Zn-螯合但具有高度选择性的 MMP-13 抑制剂。

Development of a putative Zn-chelating but highly selective MMP-13 inhibitor.

机构信息

Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, United States; Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria.

Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, United States; Department of Chemistry and Biochemistry, Queens College, Queens, NY 11367, United States; Ph.D. Programs in Chemistry and Biochemistry, The Graduate Center of the City University of New York, NY 10016, United States.

出版信息

Bioorg Med Chem Lett. 2022 Nov 15;76:129014. doi: 10.1016/j.bmcl.2022.129014. Epub 2022 Oct 4.

DOI:10.1016/j.bmcl.2022.129014

PMID:36202189

Abstract

Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S' loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 μM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.

摘要

从已知的 MMP-13 抑制剂 1 出发，我们进行了 SAR 研究，重点优化接近酶的 Zn 结合位点的相互作用。我们发现含氧化丁烷的化合物 32（MMP-13 IC=42 nM），它在体外研究中表现出完全抑制胶原分解的作用，并且在 MMP 家族中具有极好的选择性。有趣的是，对接研究表明，32 中的氧化丁烷环朝向 Zn 离子以螯合金属离子。MMP13 抑制剂的螯合特性通常与酶家族内的非选择性有关。化合物 32 是一个罕见的例子，其中选择性可以通过 S'环内相互作用的组合效应和氧化丁烷部分的螯合作用来解释。此外，进行了体内药代动力学研究，证明在大鼠膝关节滑液中 32 的浓度为 1.97 μM，这使该化合物成为进一步优化和开发骨关节炎的有前途的先导化合物。