Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives |
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| Authors: | D J Carini J V Duncia P E Aldrich A T Chiu A L Johnson M E Pierce W A Price J B Santella G J Wells R R Wexler |
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| Affiliation: | Medical Products Department, E. I. du Pont de Nemours & Company, Inc., Wilmington, Delaware 19880-0402. |
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| Abstract: | A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension. |
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