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2-苄基哌嗪：一种新型强效人碳酸酐酶抑制剂。合成、酶抑制、对映选择性、计算和晶体学研究以及一类新型降眼压药物的体内活性。

2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents.

机构信息

University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.

University of Florence, Department of Chemistry, via della Lastruccia, 50019, Sesto Fiorentino, Italy.

出版信息

Eur J Med Chem. 2018 May 10;151:363-375. doi: 10.1016/j.ejmech.2018.04.002. Epub 2018 Apr 3.

DOI:10.1016/j.ejmech.2018.04.002
PMID:29635168
Abstract

Two series of 2-benzylpiperazines have been prepared and tested for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1). The new compounds carry on one nitrogen atom of the piperazine ring a sulfamoylbenzamide group as zinc-binding moiety, and different alkyl/acyl/sulfonyl groups on the other nitrogen. Regio- and stero-isomers are described. The majority of these compounds showed Ki values in the low-medium nanomolar range against hCA I, II and IV, but not IX. In many instances interaction with the enzyme was enantioselective. The binding mode has been studied by means of X-ray crystallography and molecular modelling. Two compounds, evaluated in rabbit models of glaucoma, were able to significantly reduce intraocular pressure, making them interesting candidates for further studies.

摘要

已经制备了两个 2-苄基哌嗪系列，并对其抑制生理相关的人碳酸酐酶（hCA，EC 4.2.1.1）同型进行了测试。这些新化合物在哌嗪环的一个氮原子上带有磺酰胺苯甲酰胺基团作为锌结合部分，而在另一个氮原子上带有不同的烷基/酰基/磺酰基。本文描述了区域和立体异构体。这些化合物中的大多数对 hCA I、II 和 IV，但不是 IX，表现出中低纳摩尔范围内的 Ki 值。在许多情况下，与酶的相互作用具有对映选择性。通过 X 射线晶体学和分子建模研究了结合模式。两种在青光眼兔模型中进行评估的化合物能够显著降低眼内压，使它们成为进一步研究的有前途的候选药物。

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