• George W Farr, Christopher H Hall, Susan M Farr, Ramon Wade, Joshua M Detzel, Amielia G Adams, Jasen M Buch, Derek L Beahm, Christopher A Flask, Kui Xu, Joseph C LaManna, Paul R McGuirk, Walter F Boron, and Marc F Pelletier.
• Aeromics, Inc., Cleveland, OH 44106, USA; Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: george.farr@aeromics.com.
• Neuroscience. 2019 Apr 15; 404: 484-498.

AbstractCerebral 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.Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

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