title: Design, synthesis, structural studies, biological evaluation, and computational simulations of novel potent AT(1) 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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Gal la
authors.initials: Gl
authors.lastname: Pericot Mohr Gl
authors.forename: Andrea
authors.initials: A
authors.lastname: Gallelli
authors.forename: Milena
authors.initials: M
authors.lastname: Rizzo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.forename: Flora
authors.initials: F
authors.lastname: Ferrari
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Menziani
authors.forename: Pier G
authors.initials: PG
authors.lastname: De Benedetti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C486792:4-(4-((5,7-dimethyl-2-ethyl-3H-imidazo(4,5-b)pyridin-3-yl)methyl)phenyl)-3-(2H-tetrazol-5-yl)quinoline; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D008024:Ligands; D011687:Purines; D011725:Pyridines; D011804:Quinolines; D013777:Tetrazoles