Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant agents: Structure-activity relationship and pharmacological evaluation
Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant agents: Structure-activity relationship and pharmacological evaluation
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DOI：
10.1016/j.ejmech.2008.02.018
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发表时间：
2008-12-01
影响因子：
6.7
通讯作者：
Masereel, Bernard
中科院分区：
文献类型：
--
作者：
Thiry, Anne;Rolin, Stephanie;Masereel, Bernard
筛选茚满磺酰胺的小文库以抑制参与神经元兴奋的人碳酸酐酶（CA，EC 4.2.1.1）同种型，即同种型VII、XII和XIV。这些CA异构体正在成为设计用于治疗癫痫的药物的有趣靶点。这些茚满磺酰胺化合物对这三种亚型的抑制模式是优异的，检测到许多纳摩尔抑制剂（对hCA VII的K（I）在0.78-10 nM范围内;对hCA XII的K（I）在0.32-56 nM范围内，对hCA XIV的K（I）在0.47-1030 nM范围内）。对小鼠进行的最大电休克发作（MES）试验显示，某些化合物具有良好的抗惊厥活性，在50 mg/kg剂量下，可保护小鼠免受50-62.5%范围内的惊厥。同时，这些磺胺类药物的血脑屏障被动渗透也估计通过使用计算方法。(C)2008年，Elsevier Masson SAS。All rights reserved.
A small library of indanesulfonamides was screened for the inhibition of the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in neuronal excitation, that is, isoforms VII, XII and XIV. These CA isoforms are becoming interesting target for the design of agents useful for the treatment of epilepsy. The inhibition pattern of these indanesulfonamide compounds towards these three isoforms was excellent, with many nanomolar inhibitors detected (K(I)s in the range of 0.78-10 nM against hCA VII; 0.32-56 nM against hCA XII, and 0.47-1030 nM against hCA XIV, respectively). The maximal electroshock seizure (MES) test performed on mice showed a good anticonvulsant activity for some compounds which protected the mice against convulsions in the 50-62.5% range at a dose of 50 mg/kg. In parallel, the blood-brain barrier passive permeation of these sulfonamides was also estimated by using a computational approach. (C) 2008 Elsevier Masson SAS. All rights reserved.