Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies,Journal of Medicinal Chemistry

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Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01236
Olivier Bezençon ₁ , Bibia Heidmann ₁ , Romain Siegrist ₁ , Simon Stamm ₁ , Sylvia Richard ₁ , Davide Pozzi ₁ , Olivier Corminboeuf ₁ , Catherine Roch ₁ , Melanie Kessler ₁ , Eric A. Ertel ₁ , Isabelle Reymond ₁ , Thomas Pfeifer ₁ , Ruben de Kanter ₁ , Michael Toeroek-Schafroth ₁ , Luca G. Moccia ₁ , Jacques Mawet ₁ , Richard Moon ₁ , Markus Rey ₁ , Bruno Capeleto ₁ , Elvire Fournier ₁

Affiliation

We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

中文翻译：

发现有效的，选择性的T型钙通道阻滞剂作为治疗全身性癫痫的候选药物

我们在这里报告N-（1-苄基-1 H-吡唑-3-基）-2-苯基乙酰胺衍生物作为有效的，选择性的，穿透脑的T型钙通道阻滞剂的发现和药理学表征。优化主要集中在溶解度，大脑渗透性以及寻找在Ames测试中呈阴性的氨基吡唑代谢物。这导致化合物66b（ACT-709478）的制备和完整表征，该化合物已被选择作为临床候选药物。

更新日期：2017-11-21

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