A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists

Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 36; no. 22; pp. 3371 - 3380
Main Authors:	Bernhart, Claude A, Perreaut, Pierre M, Ferrari, Bernard P, Muneaux, Yvette A, Assens, Jean Louis A, Clement, Jacques, Haudricourt, Frederique, Muneaux, Claude F, Taillades, Joelle E, Vignal, Marie-Aimee, Gougat, Jean, Guiraudou, Pierre R, Lacour, Colette A, Roccon, Alain, Cazaubon, Catherine F, Breliere, Jean-Claude, Le Fur, Gerard, Nisato, Dino
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-10-1993
Subjects:	Angiotensin II - metabolism Angiotensin Receptor Antagonists Animals Biphenyl Compounds - chemical synthesis Biphenyl Compounds - pharmacology Chemistry Exact sciences and technology Female Heterocyclic compounds Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings Imidazoles - chemical synthesis Imidazoles - pharmacology In Vitro Techniques Irbesartan Macaca fascicularis Male Organic chemistry Preparations and properties Rabbits Rats Rats, Sprague-Dawley Receptors, Angiotensin - metabolism Sensitivity and Specificity Structure-Activity Relationship Tetrazoles - chemical synthesis Tetrazoles - pharmacology Imidazole derivatives Five membered ring Rat Regioselectivity Nitrogen heterocycle Rodentia Lactam Oral administration Alkylation Spiran Vertebrata Mammalia Structure activity relation Animal Angiotensin antagonist Angiotensin II Monocyclic compound Biological receptor
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Summary:	Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.
Bibliography:	ark:/67375/TPS-M5NZNGVP-Q istex:581AE1BA47C713E1023AC683F205DAADA2141F47 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00074a018