Design, Synthesis, Strucural Studies, Biological Evaluation, and Computational Simulations of Novel Potent AT1 Angiotensin II Receptor Antagonists Based on the 4-Phenylquinoline Structure

Novel AT1 receptor antagonists bearing substituted 4-phenylquinoline moieties instead of theclassical biphenyl fragment were designed and synthesized as the first step of an investigationdevoted to the development of new antihypertensive agents and to the understanding of themolecular basis of their pharmacodynamic and pharmacokinetic properties. The newlysynthesized compounds were tested for their potential ability to displace [125I]Sar1,Ile8-Ang IIspecifically bound to AT1 receptor in rat hepatic membranes. These AT1 receptor binding studiesrevealed nanomolar affinity in several of the compounds under study. The most potent ligands4b,t were found to be equipotent with losartan and possessed either a 3-tetrazolylquinoline ora 2-amino-3-quinolinecarboxylic moiety, respectively. Moreover, some selected compounds wereevaluated for antagonism of Ang II-induced contraction in rabbit aortic strips, and the mostpotent compounds in the binding test 4b,t were slightly more potent than losartan in inhibitingAng II-induced contraction. Finally, the most relevant structure-affinity relationship data wererationalized by means of computational studies performed on the isolated ligands as well asby computational simulations on the ligands complexed with a theoretical AT1 receptor model.