Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury
Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury
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DOI：
10.1016/j.neuroscience.2019.01.034
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发表时间：
2019-04-15
期刊：
影响因子：
3.3
通讯作者：
Pelletier, Marc F.
中科院分区：
文献类型：
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作者：
Farr, George W.;Hall, Christopher H.;Pelletier, Marc F.
缺血性中风中的脑水肿可导致颅内压升高、脑血流量减少和神经元死亡。不幸的是，目前脑水肿的治疗方法要么无效，要么高度侵入性。在细胞毒性和随后的离子性脑水肿的发展过程中，水通过移动穿过完整的血脑屏障并穿过星形胶质细胞端足处的水通道蛋白4（AQP 4）进入脑。使用表达AQP 4的细胞，我们筛选了小分子文库中的抑制剂，以降低AQP 4介导的水渗透性。其他功能测定用于验证AQP 4抑制，并确定了一个有前途的药物化学结构系列。这些努力提高了效力，并揭示了我们命名为AER-270的化合物，N-[3，5-双（三氟甲基）苯基]-5-氯-2-羟基苯甲酰胺。AER-270和溶解度增强的前药AER-271 2-{[3，5-双（三氟甲基）苯基]氨基甲酰基}-4-氯苯基二氢磷酸盐在两种CNS损伤并发脑水肿模型（水中毒和大脑中动脉闭塞模型）中改善神经功能结局并减轻肿胀。(C)2019年IBRO。由爱思唯尔有限公司发布。保留所有权利。
Cerebral edema in ischemic stroke can lead to increased intracranial pressure, reduced cerebral blood flow and neuronal death. Unfortunately, current therapies for cerebral edema are either ineffective or highly invasive. During the development of cytotoxic and subsequent ionic cerebral edema water enters the brain by moving across an intact blood brain barrier and through aquaporin-4 (AQP4) at astrocyte endfeet. Using AQP4-expressing cells, we screened small molecule libraries for inhibitors that reduce AQP4-mediated water permeability. Additional functional assays were used to validate AQP4 inhibition and identified a promising structural series for medicinal chemistry. These efforts improved potency and revealed a compound we designated AER-270, N-[3,5-bis (trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. AER-270 and a prodrug with enhanced solubility, AER-271 2-{[3,5-Bis(trifluoromethyl) phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, improved neurological outcome and reduced swelling in two models of CNS injury complicated by cerebral edema: water intoxication and ischemic stroke modeled by middle cerebral artery occlusion. (C) 2019 IBRO. Published by Elsevier Ltd. All rights reserved.