Document Detail

Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents.
MedLine Citation:
PMID:  18391097     Owner:  NLM     Status:  MEDLINE    
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<0.05). Chronic infusion of the xanthenone (120 microg/day) resulted in a modest decrease in the spontaneously hypertensive rat blood pressure (17 mm Hg; 2-way ANOVA; P<0.05), whereas it had no effect in Wistar-Kyoto rats. Strikingly, the decrease in blood pressure was also associated with improvements in cardiac function and reversal of myocardial, perivascular, and renal fibrosis in the spontaneously hypertensive rats. We conclude that structure-based screening can help identify compounds that activate ACE2, decrease blood pressure, and reverse tissue remodeling. Administration of ACE2 activators may be a valid strategy for antihypertensive therapy.
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; Mohan K Raizada
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-04-07
Journal Detail:
Title:  Hypertension     Volume:  51     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-04-18     Completed Date:  2008-05-07     Revised Date:  2014-01-08    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1312-7     Citation Subset:  IM    
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MeSH Terms
Antihypertensive Agents / chemistry,  pharmacology*,  therapeutic use*
Blood Pressure / drug effects,  physiology
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Design
Enzyme Activators / chemistry,  pharmacology*,  therapeutic use*
Heart / drug effects,  physiology
Hypertension / drug therapy*,  physiopathology
Peptidyl-Dipeptidase A / drug effects*,  metabolism
Rats, Inbred SHR
Rats, Inbred WKY
Resorcinols / pharmacology,  therapeutic use
Structure-Activity Relationship
Xanthenes / pharmacology,  therapeutic use
Grant Support
Reg. No./Substance:
0/Antihypertensive Agents; 0/Enzyme Activators; 0/Resorcinols; 0/Xanthenes; EC A; EC 3.4.17.-/angiotensin converting enzyme 2

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