Synthesis and angiotensin II receptor antagonist activity of C-linked pyrazole derivatives
| Autor: | Jean-Marie Teulon, Michele Cazes, Francois Caussade, M. Kirchner, Eric Nicolai, Joel Goyard, A. Versigny, Angela Virone-Oddos, Alix Cloarec, Gerard Cure |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
medicine.medical_specialty
Hypertension Renal Magnetic Resonance Spectroscopy Tetrazoles Angiotensin II receptor antagonist Blood Pressure Losartan Angiotensin Receptor Antagonists In vivo Oral administration Internal medicine Drug Discovery medicine Animals Receptor Antihypertensive Agents Chemistry Biphenyl Compounds Antagonist Imidazoles Biological activity General Chemistry General Medicine Angiotensin II Rats Endocrinology Pyrazoles medicine.drug |
| Zdroj: | Chemicalpharmaceutical bulletin. 42(8) |
| ISSN: | 0009-2363 |
| Popis: | The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These 5-O-substituted and 5-C-substituted 3-alkylpyrazole derivatives represent a new series of antagonists and have led to to the discovery of compounds with potent oral antihypertensive activity in a renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors. In vivo structure-activity relationship study has shown the importance of the 4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl moiety for oral activity and the critical role of alkyl substituents at the 1- or 2-position. In the case of oral administration, 5-C derivatives were found to be, on the whole, more potent than 5-O derivatives. UP 221-78, 5-hydroxymethyl-3-n-propyl-1-(2, 2, 2-trifluoroethyl)-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-]methyl]-1H-pyrazole (79), displayed equivalent antihypertensive activity to the well known antagonist Losartan at 3 mg/kg p.o. in renal artery-ligated rats, with maximal decreases in mean arterial pressure of 60 and 63 mmHg for Losartan and UP 221-78, respectively. |
| Databáze: | OpenAIRE |
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