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

Article abstract of DOI:10.1021/jm00019a005

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.