Fresneau P, Cussac M, Morand J M, Szymonski B, Tranqui D, Leclerc G
Laboratoire de Chimie Thérapeutique and Laboratoire de Chimie Organique, Groupe de Pharmacochimie Moléculaire, EP811-CNRS, France.
J Med Chem. 1998 Nov 19;41(24):4706-15. doi: 10.1021/jm9801399.
A series of 2,4-dioxo-5-(2-naphthylmethylene)-3-thiazolidineacetic acids and 2-thioxo analogues have been prepared as aldose reductase inhibitors. In vitro inhibitory activities of bovine lens aldose reductase were determined by a conventional method. 1-Naphthyl-substituted derivatives of the 2-thioxo series were the more potent inhibitors (IC50 congruent with 10 nM) with similar activity to that of Epalrestat. Structural analysis, especially by X-ray crystallography of two selected compounds, and molecular modeling comparisons with Zopolrestat were performed. These results provide explanations of the good activity of the inhibitor, the preference for 1-naphthyl-substituted compounds, and the nature of molecular interactions in these systems.
一系列2,4-二氧代-5-(2-萘基亚甲基)-3-噻唑烷乙酸及其2-硫代类似物已被制备为醛糖还原酶抑制剂。采用常规方法测定了牛晶状体醛糖还原酶的体外抑制活性。2-硫代系列的1-萘基取代衍生物是更有效的抑制剂（IC50约为10 nM），其活性与依帕司他相似。对两种选定化合物进行了结构分析，尤其是通过X射线晶体学分析，并与唑泊司他进行了分子模拟比较。这些结果解释了抑制剂的良好活性、对1-萘基取代化合物的偏好以及这些体系中分子相互作用的性质。
