- Derivatives of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins as orally active angiotensin II receptor antagonists
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A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Aug II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Aug 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 AT2 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 Aug 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 Aug II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.
- Edmunds,Klutchko,Hamby,Bunker,Connolly,Winters,Quin III,Sircar,Hodges,Panek,Keiser,Doherty
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p. 3759 - 3771
(2007/10/03)
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- SUBSTITUTED-5-METHYLIDENE HYDANTOINS WITH AT1 RECEPTOR ANTAGONIST PROPERTIES
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Substituted 1-benzylimidazole-5-methylidene hydantoins are disclosed as well as methods of preparing them, pharmaceutical compositions containing them, and method of using them. Intermediates useful in the preparation of the compounds of the invention are also disclosed and synthetic methods for preparing the novel intermediates. The compounds are useful as antagonists of angiotensin II and thus are useful in the control of hypertension, hyperaldosteronism, congestive heart failure, surgically induced vascular smooth muscle proliferation, and glaucoma.
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