Document Detail


Synthesis and angiotensin II receptor antagonist activity of C-linked pyrazole derivatives.
MedLine Citation:
PMID:  7954914     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 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.
Authors:
E Nicolaï; G Curé; J Goyard; M Kirchner; J M Teulon; A Versigny; M Cazes; A Virone-Oddos; F Caussade; A Cloarec
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Chemical & pharmaceutical bulletin     Volume:  42     ISSN:  0009-2363     ISO Abbreviation:  Chem. Pharm. Bull.     Publication Date:  1994 Aug 
Date Detail:
Created Date:  1994-12-06     Completed Date:  1994-12-06     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0377775     Medline TA:  Chem Pharm Bull (Tokyo)     Country:  JAPAN    
Other Details:
Languages:  eng     Pagination:  1617-30     Citation Subset:  IM    
Affiliation:
CARPIBEM, Rueil Malmaison, France.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antihypertensive Agents / chemical synthesis*,  pharmacology,  therapeutic use
Biphenyl Compounds / pharmacology,  therapeutic use
Blood Pressure / drug effects*
Hypertension, Renal / drug therapy*
Imidazoles / pharmacology,  therapeutic use
Losartan
Magnetic Resonance Spectroscopy
Pyrazoles / chemical synthesis,  chemistry*,  pharmacology,  therapeutic use
Rats
Receptors, Angiotensin / antagonists & inhibitors*
Tetrazoles / chemistry,  pharmacology,  therapeutic use
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/Biphenyl Compounds; 0/Imidazoles; 0/Pyrazoles; 0/Receptors, Angiotensin; 0/Tetrazoles; 0/UP 221-78; 114798-26-4/Losartan

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