Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives
| Autor: | Paul E. Aldrich, William A. Price, J V Duncia, J B Santella rd, Ruth R. Wexler, Michael E. Pierce, Gregory J. Wells, Andrew T. Chiu, David J. Carini, Alexander L. Johnson |
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| Rok vydání: | 1991 |
| Předmět: |
Male
Angiotensin receptor Chemical Phenomena Stereochemistry Carboxylic acid Administration Oral Tetrazoles Losartan Angiotensin Receptor Antagonists Structure-Activity Relationship chemistry.chemical_compound Oral administration Adrenal Glands Drug Discovery medicine Animals Tetrazole Hydroxymethyl Antihypertensive Agents chemistry.chemical_classification Receptors Angiotensin Molecular Structure Biphenyl Compounds Imidazoles Rats Inbred Strains Angiotensin II Rats Chemistry chemistry Hypertension Molecular Medicine medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 34:2525-2547 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00112a031 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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