Angiotensin Antagonists

Hypertension Exercise Program

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Mark J. Robertson

Astra Charnwood, Loughborough, Leicestershire, England I. Introduction

Any remaining questions that may have challenged the pathophysiological importance of the renin-angiotensin system (RAS) have been dispelled by the established and growing success of the angiotensin converting enzyme inhibitors (ACEIs) in the clinic. For example, captopril, first introduced in 1981, and then enalapril have become established as front-line treatments for hypertension (1,2), and exciting results have emerged from large clinical trials regarding the usefulness of ACEIs in congestive heart failure (CHF) and diabetic nephropathy (3-6). The realization that ACEIs would have tremendous commercial success caused an enthusiastic response from the pharmaceutical industry to identify other opportunities to interfere therapeutically with the RAS. It was from this intense period of research, during the 1980s, that the first nonpeptide angiotensin receptor antagonists were developed. The prototype compound and most clinically advanced of these, losartan (otherwise known as Ex 89, Dup-89, DuP753, or MK-954), is now marketed for the treatment of hypertension and in phase III trials for heart failure. Many other related ligands are also in various stages of clinical and preclinical development.

This overview outlines the developing rationale for the angiotensin receptor antagonists, as well as their evolution from peptide origins to clinically viable therapeutic agents. It does not, however, attempt to provide an extensive catalog of nonpeptide angiotensin receptor antagonists: descriptions of more complete structure-activity relationships can be found elsewhere (e.g., Refs. 7-12).

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