6-SUBSTITUTED BENZIMIDAZOLES AS NEW NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS, BIOLOGICAL-ACTIVITY, AND STRUCTURE-ACTIVITY-RELATIONSHIPS

Starting from the recently reported nonpeptidic angiotensin II (AII) r eceptor antagonists DuP 753 (1) and Exp 7711 (2), we have designed and investigated novel substituted benzimidazoles. Systematic variation o f several substituents at the benzimidazole ring positions 4-7 led to the finding that substitution in position 6 with acylamino groups resu lts in highly active AII antagonists. Compounds with 6-membered lactam or sultam substitutents in position 6 of benzimidazole showed recepto r activities in the low nanomolar range but were only weakly active wh en given orally to rats. In contrast, analogous substitution of the be nzimidazole moiety with basic heterocycles resulted in potent AII anta gonists which were also well absorbed after oral application. The most active compound of this series, 33 (BIBR 277), was selected as a cand idate for clinical development. On the basis of molecular modeling stu dies a binding model of this new class of AII antagonists to the AT1 r eceptor is proposed.