Nonpeptide Angiotensin II Receptor Antagonists: Synthesis, Biological Activities, and Structure−Activity Relationships of Imidazole-5-carboxylic Acids Bearing Alkyl, Alkenyl, and Hydroxyalkyl Substituents at the 4-Position and Their Related Compounds
| Autor: | Youji Furukawa, Masahiro Ikeda, Yasuo Shimoji, Yoshiko Kitahara, Shuichi Miyamoto, Yoshiya Amemiya, Takuro Kanazaki, Toshio Sada, Makoto Mizuno, Hiroyuki Koike, Fujimoto Koichi, Hiroaki Yanagisawa |
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| Rok vydání: | 1996 |
| Předmět: |
Male
Models Molecular Angiotensin receptor Molecular model Stereochemistry Carboxylic acid Molecular Sequence Data Molecular Conformation Biphenyl derivatives Biological Availability In Vitro Techniques Chemical synthesis Angiotensin Receptor Antagonists Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Imidazole Amino Acid Sequence Rats Wistar Antihypertensive Agents Alkyl chemistry.chemical_classification Receptors Angiotensin Molecular Structure Angiotensin II Imidazoles Acetylation Rats Kinetics chemistry Adrenal Cortex Molecular Medicine Cattle |
| Zdroj: | Journal of Medicinal Chemistry. 39:323-338 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm950450f |
| Popis: | A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2'-1H-tetrazol-5- ylbiphenyl-4-yl)-methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken. |
| Databáze: | OpenAIRE |
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