The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.
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