NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS, IN-VITRO ACTIVITY, AND MOLECULAR MODELING STUDIES OF N-[(HETEROBIARYL)METHYL]IMIDAZOLES

With the aim of explaining the influence of the structural changes on the biphenylic moiety on the activity, a series of N-[(heterobiaryl)me thyl]imidazoles (I), constructed on the model of DuPont compounds by r eplacing either the central or terminal phenyl ring with a heteroaroma tic one, such as furan, thiophene, thiazole, and pyridine, was synthes ized. Compared to the reference DuPont compound (EXP-7711), all the he terobiaryl derivatives showed a reduced potency both in receptor bindi ng (rat adrenal capsular membranes) and in the functional assay (angio tensin II-induced contraction of rabbit aorta strips). The lower activ ity was justified by the extensive molecular modeling studies, which t ook into consideration the conformational and electrostatic features o f several heterobiaryl derivatives. On the basis of the results obtain ed, it was hypothesized that the central aromatic ring of the biarylic portion works as a spacer, orienting in the right way the terminal ph enyl ring, whose electronic distribution is, instead, crucial to its f itting well with a lipophilic pocket at the receptor site.