DIPHENYLPROPIONIC ACIDS AS NEW AT(1) SELECTIVE ANGIOTENSIN-II ANTAGONISTS

Citation
C. Almansa et al., DIPHENYLPROPIONIC ACIDS AS NEW AT(1) SELECTIVE ANGIOTENSIN-II ANTAGONISTS, Journal of medicinal chemistry, 39(11), 1996, pp. 2197-2206
Citations number
39
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
39
Issue
11
Year of publication
1996
Pages
2197 - 2206
Database
ISI
SICI code
0022-2623(1996)39:11<2197:DAANAS>2.0.ZU;2-X
Abstract
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.