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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 12, 2004; DOI: 10.1124/jpet.103.055855

0022-3565/04/3091-275-284$20.00
JPET 309:275-284, 2004
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CARDIOVASCULAR

Novel Dual Action AT1 and ETA Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Mark C. Kowala, Natesan Murugesan, John Tellew, Kenneth Carlson, Hossain Monshizadegan, Carol Ryan, Zhengxiang Gu, Bridgette Kane, Leena Fadnis, Rose Ann Baska, Sophie Beyer, Susan Arthur, Kenneth Dickinson, Donglu Zhang, Mark Perrone, Pam Ferrer, Mary Giancarli, Jergen Baumann, Eileen Bird, Balkrushna Panchal, Yifan Yang, Nick Trippodo, Joel Barrish, and John E. Macor

Departments of Metabolic and Cardiovascular Drug Discovery (M.C.K., K.C., H.M., C.R., R.A.B., S.B., S.A., K.D., D.Z., M.P., P.F., M.G., J.B., N.T.) and Discovery Chemistry (N.M., J.T., H.M., Z.G., B.K., L.F., J.B., J.E.M.), Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey

Angiotensin II and endothelin-1 activate their respective AT1 and ETA receptors on vascular smooth muscle cells, producing vasoconstriction, and both peptides are implicated in the pathogenesis of essential hypertension. Angiotensin II potentiates the production of endothelin, and conversely endothelin augments the synthesis of angiotensin II. Both AT1 and ETA receptor antagonists lower blood pressure in hypertensive patients; thus, a combination AT1/ETA receptor antagonist may have greater efficacy and broader utility compared with each drug alone. By rational drug design a biphenyl ETA receptor blocker was modified to acquire AT1 receptor antagonism. These compounds (C and D) decreased Sar-Ile-Angiotensin II binding to AT1 receptors and endothelin-1 binding to ETA receptors, and compound C inhibited angiotensin II- and endothelin-1-mediated Ca2+ transients. In rats compounds C and D reduced blood pressure elevations caused by intravenous infusion of angiotensin II or big endothelin-1. Compound C decreased blood pressure in Na+-depleted spontaneously hypertensive rats and in rats with mineralocorticoid hypertension. Compound D was more efficacious than AT1 receptor antagonists at reducing blood pressure in spontaneously hypertensive rats, and its superiority was likely due to its partial blockade of ETA receptors. Therefore compounds C and D are novel agents for treating a broad spectrum of patients with essential hypertension and other cardiovascular diseases.

Received June 18, 2003; accepted November 19, 2003.

Address correspondence to: Dr. Mark C. Kowala, Department of Cardiovascular Pharmacology, 025-289, Pfizer Global Research and Development, 2800 Plymouth Rd., Ann Arbor MI 48105. E-mail: mark.kowala{at}pfizer.com






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