title: Further studies on imidazo[4,5-b]pyridine AT1 angiotensin II receptor antagonists. Effects of the transformation of the 4-phenylquinoline backbone into 4-phenylisoquinolinone or 1-phenylindene scaffolds.
abstract: The 4-phenylquinoline fragment of novel AT(1) receptor antagonists 4 based on imidazo[4,5-b]pyridine moiety was replaced by 4-phenylisoquinolinone (compounds 5) or 1-phenylindene (compounds 6) scaffolds to investigate the structure-activity relationships. Binding studies showed that most of the synthesized compounds display high affinity for the AT(1) receptor. Because of the in vitro high potency of carboxylic acids 5b,f, they were evaluated in permeability (in Caco-2 cells) and in pharmacokinetic studies in comparison with quinoline derivatives 4b,i,j,k. The studies showed that these compounds are characterized by rapid excretion, low membrane permeability, and low oral bioavailability. The structure optimization of the indene derivatives led to compounds 6e,f possessing interesting AT(1) receptor affinities. Optimization produced polymerizing AT(1) receptor ligand 6c, which forms a thermoreversible polymer (poly-6c) and is released from the latter by a temperature-dependent kinetics. The results suggest the possibility of developing novel polymeric prodrugs based on a new release mechanism. Finally, a set of 34 AT(1) receptor antagonists was used as a new test for the evaluation of the predictive capability of the previously published qualitative and quantitative pharmacophore models.
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
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.forename: Simone
authors.initials: S
authors.lastname: Galeazzi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
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: Eva M
authors.initials: EM
authors.lastname: Kleinrath
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Massimo
authors.initials: M
authors.lastname: Valoti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D018938:Caco-2 Cells; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D006865:Hydrogenation; D066298:In Vitro Techniques; D007192:Indenes / Q000737:chemistry*; D007202:Indicators and Reagents; D007408:Intestinal Absorption; D007546:Isoquinolines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D011237:Predictive Value of Tests; D011687:Purines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007192:Indenes; D007202:Indicators and Reagents; D007546:Isoquinolines; D011687:Purines; D015363:Quinolones; C064191:1H-imidazo(4,5-b)pyridine