4-DIAZINYLIMIDAZOLES AND 4-PYRIDINYLIMIDAZOLES - POTENT ANGIOTENSIN-II ANTAGONISTS - A STUDY OF THEIR ACTIVITY AND COMPUTATIONAL CHARACTERIZATION

A series of N-[biphenylyl(tetrazolyl)methyl]-2-butylimidazoles contain ing variously substituted diazine or pyridine moieties either as their free bases or N-oxide derivatives attached to the 4-position of the i midazole ring was synthesized and tested for interaction with the AT(1 ) receptors of rat adrenal cortex membranes (receptor binding assay). Some compounds were then chosen for further evaluation in vivo in the A II-induced presser response in conscious normotensive rats. The most potent in the AT(1) binding assay were found to be compounds in which the diazine or pyridine ring nitrogen is adjacent to the point of att achment between the two heteroaromatic rings such as 6-dimethylpyrazin -2-yl)-1-[[2'-(1H-tetrazol-5-yl)- biphenyl-4-yl]methyl]-1H-imidazole ( 3b) or H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole (6c). The bi nding affinities and oral activities of the pyridine N-oxide imidazole s in which a stabilizing group ortho to the pyridine ring nitrogen is present were markedly improved as in tyl-4-[(3-methoxycarbonyl)-6-meth yl-N-oxopyridin-2 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole 3 1b. Molecular modeling studies were carried out to determine the molec ular electrostatic potential values of related model systems and to co rrelate their receptor interaction energies with the observed activiti es of our compounds.