A. Salimbeni et al., NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS, IN-VITRO ACTIVITY, AND MOLECULAR MODELING STUDIES OF N-[(HETEROBIARYL)METHYL]IMIDAZOLES, Journal of medicinal chemistry, 37(23), 1994, pp. 3928-3938
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.