Derivatives of 5-[[1-4(4-carboxybenzyl)imidazolyl]methylidene]hydantoins as orally active angiotensin II receptor antagonists

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-09, Vol.38 (19), p.3759-3771
Main Authors: Edmunds, Jeremy J, Klutchko, Sylvester, Hamby, James M, Bunker, Amy M, Connolly, Cleo J. C, Winters, R. Thomas, Quin, John, Sircar, Ila, Hodges, John C
Format: Article
Language:English
Subjects:
Administration, Oral
Angiotensin II - antagonists & inhibitors
Angiotensin II - metabolism
Angiotensin Receptor Antagonists
Animals
Antihypertensive Agents - chemical synthesis
Antihypertensive Agents - chemistry
Antihypertensive Agents - metabolism
Antihypertensive Agents - pharmacology
Aorta - drug effects
Biological and medical sciences
Blood Pressure - drug effects
Haplorhini
Hydantoins - chemical synthesis
Hydantoins - chemistry
Hydantoins - metabolism
Hydantoins - pharmacology
Hypertension - drug therapy
In Vitro Techniques
Male
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Rabbits
Rats
Rats, Sprague-Dawley
Receptors, Angiotensin - metabolism
Structure-Activity Relationship
Vasoconstriction - drug effects
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Description
Summary:A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00019a005