C. Almansa et al., DIPHENYLPROPIONIC ACIDS AS NEW AT(1) SELECTIVE ANGIOTENSIN-II ANTAGONISTS, Journal of medicinal chemistry, 39(11), 1996, pp. 2197-2206
The synthesis and pharmacological evaluation of a new series of potent
AT(1) selective diphenylpropionic acid nonpeptide angiotensin II rece
ptor antagonists are reported. The new compounds were evaluated for in
vitro AT(1) (rat liver) and AT(2) (rat adrenal) binding affinity as w
ell as for in vivo inhibition of angiotensin II-induced increase in me
an arterial blood pressure in pithed rats. Unsaturation of the dipheny
lpropionic acids as well as substitution or replacement by alkyl group
s 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 res
ultant diastereoisomers (R,R*) being ca. 10-fold more active than the
other (R,S*). Oral evaluation of the most active compounds in a furo
semide-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 losa
rtan but faster onset of action and somewhat greater oral activity, pr
esumably due to its improved bioavailability.