DERIVATIVES OF 5-[[1-(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 AT(1) receptor and negligible affinity for the AT(2) receptor. Preferred substituents include an n-butyl at R(1) and an alkyl or heteroarylmethyl substituent at R(2). The selection of the Ra substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT(1) binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT(1) 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.