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.
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.
Cappelli
Andrea
A
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
Pericot Mohr
Gal la
Gl
Giuliani
Germano
G
Galeazzi
Simone
S
Anzini
Maurizio
M
Mennuni
Laura
L
Ferrari
Flora
F
Makovec
Francesco
F
Kleinrath
Eva M
EM
Langer
Thierry
T
Valoti
Massimo
M
Giorgi
Gianluca
G
Vomero
Salvatore
S
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
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