José A. Hernández Prada; Anderson J. Ferreira; Michael J. Katovich; Vinayak Shenoy; Yanfei Qi; Robson A.S. Santos; Ronald K. Castellano; Andrew J. Lampkins; Vladimir Gubala; David A. Ostrov; and Mohan K. Raizada, Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents
Hypertension. 51(5):1312-7, 2008-05-08

Abstract [-]: Angiotensin-converting enzyme 2 (ACE2) is a key renin-angiotensin system enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system, and its overexpression by gene transfer is beneficial in cardiovascular disease. Therefore, our objectives were 2-fold: to identify compounds that enhance ACE2 activity using a novel conformation-based rational drug discovery strategy and to evaluate whether such compounds reverse hypertension-induced pathophysiologies. We used a unique virtual screening approach. In vitro assays revealed 2 compounds (a xanthenone and resorcinolnaphthalein) that enhanced ACE2 activity in a dose-dependent manner. Acute in vivo administration of the xanthenone resulted in a dose-dependent transient and robust decrease in blood pressure (at 10 mg/kg, spontaneously hypertensive rats decreased 71±9 mm Hg and Wistar-Kyoto rats decreased 21±8 mm Hg; P

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