Design and Pharmacology of Dual Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibitors

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Abstract
Angiotensin converting enzyme (ACE) inhibitors are important therapeutic agents for the management of hypertension and congestive heart failure (CHF). Although the therapeutic effects of neutral endopeptidase (NEP) inhibitors (i.e. blood pressure lowering, natriuresis, diuresis) in patients have been unimpressive, experimental and clinical evidence suggests that concomitant blockade of the renin-angiotensin­ aldosterone system (RAAS) would be beneficial. Therefore, with the expectation that combined inhibition of ACE and NEP could provide therapeutic advantages over selective inhibitors of either enzyme in the treatment of hypertension and CHF, a substantial research effort has been devoted to the design of single molecules that display dual ACE/NEP inhibitory activities. Such endeavor benefited from the opportunity that both enzymes belong to the same zinc metalloprotease superfamily. This review outlines various recent successful approaches in the design of dual inhibitors, summarizes the pharmacological properties of selected compounds, and provides an outlook on the therapeutic potential of these new agents for the treatment of human cardiovascular diseases.

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