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)methyl]imidazoles (I), constructed on the model of DuPont compounds by replacing either the central or terminal phenyl ring with a heteroaromatic one, such as furan, thiophene, thiazole, and pyridine, was synthesized. Compared to the reference DuPont compound (EXP-7711), all the heterobiaryl derivatives showed a reduced potency both in receptor binding (rat adrenal capsular membranes) and in the functional assay (angiotensin II-induced contraction of rabbit aorta strips). The lower activity was justified by the extensive molecular modeling studies, which took into consideration the conformational and electrostatic features of several heterobiaryl derivatives. On the basis of the results obtained, it was hypothesized that the central aromatic ring of the biarylic portion works as a spacer, orienting in the right way the terminal phenyl ring, whose electronic distribution is, instead, crucial to its fitting well with a lipophilic pocket at the receptor site.
Medicinal Chemistry Department, Istituto Lusofarmaco, Milano, Italy.
A
A
Salimbeni
R
R
Canevotti
F
F
Paleari
F
F
Bonaccorsi
A R
AR
Renzetti
L
L
Belvisi
G
G
Bravi
C
C
Scolastico
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles