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

Abstract

Novel AT(1) receptor antagonists bearing substituted 4-phenylquinoline moieties instead of the classical biphenyl fragment were designed and synthesized as the first step of an investigation devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I]Sar(1),Ile(8)-Ang II specifically bound to AT(1) receptor in rat hepatic membranes. These AT(1) receptor binding studies revealed nanomolar affinity in several of the compounds under study. The most potent ligands 4b,t were found to be equipotent with losartan and possessed either a 3-tetrazolylquinoline or a 2-amino-3-quinolinecarboxylic moiety, respectively. Moreover, some selected compounds were evaluated for antagonism of Ang II-induced contraction in rabbit aortic strips, and the most potent compounds in the binding test 4b,t were slightly more potent than losartan in inhibiting Ang II-induced contraction. Finally, the most relevant structure-affinity relationship data were rationalized by means of computational studies performed on the isolated ligands as well as by computational simulations on the ligands complexed with a theoretical AT(1) receptor model.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Eprosartan, the ARB with the most differentiated structure, replaces biphenyl-tetrazole with benzoic acid. Thus, ARBs are similar in this region (Cappelli et al, 2004), with each of the ARBs sharing a hydrophobic interaction between the phenyl rings and the receptor along with an ionic interaction of the acidic moiety with basic residues (Mire et al, 2005). At the other end of the molecule, where losartan has imidazole with Cl and COOH substituents, ARBs have a greater variety of structures that may explain differences.…”

7TM Receptors

“…Novel AT 1 receptor antagonists bearing substituted 4-phenylquinoline moieties have recently been designed and synthesized. The best of these compounds bind to AT 1 receptors with nanomolar affinity and are slightly more potent than losartan in functional studies (Cappelli et al, 2004). [4,5,6]…”

Synthesis and AT1 affinity evaluation of benzamidophenyl analogs of known AT1 receptor ligands with similar aromatic skeleton

“…Rat liver membranes were prepared by differential centrifugation, as previously described. 13 Briefly, liver was dissected free of fatty tissue and minced accurately with small scissors, and then about 3g -angiotensin II (Perkin Elmer life Sciences). Non specific binding was measured in the presence of 1 µM angiotensin II and represented 5-10% of total binding.…”