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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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 3rd, G J Wells, R R Wexler |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 34
Issue 8
Pg. 2525-47
(Aug 1991)
ISSN: 0022-2623 [Print] United States |
PMID | 1875348
(Publication Type: Journal Article)
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Chemical References |
- Angiotensin Receptor Antagonists
- Antihypertensive Agents
- Biphenyl Compounds
- Imidazoles
- Receptors, Angiotensin
- Tetrazoles
- Losartan
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Topics |
- Administration, Oral
- Adrenal Glands
(metabolism)
- Angiotensin Receptor Antagonists
- Animals
- Antihypertensive Agents
(chemical synthesis, therapeutic use)
- Biphenyl Compounds
(chemical synthesis, metabolism, therapeutic use)
- Chemical Phenomena
- Chemistry
- Hypertension
(drug therapy)
- Imidazoles
(chemical synthesis, metabolism, therapeutic use)
- Losartan
- Male
- Molecular Structure
- Rats
- Rats, Inbred Strains
- Receptors, Angiotensin
(metabolism)
- Structure-Activity Relationship
- Tetrazoles
(chemical synthesis, therapeutic use)
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