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
journal contributionposted on 02.11.2006, 00:00 by Andrea Cappelli, Gal.la Pericot Mohr, Germano Giuliani, Simone Galeazzi, Maurizio Anzini, Laura Mennuni, Flora Ferrari, Francesco Makovec, Eva M. Kleinrath, Thierry Langer, Massimo Valoti, Gianluca Giorgi, Salvatore Vomero
The 4-phenylquinoline fragment of novel AT1 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 AT1 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 AT1 receptor affinities. Optimization produced polymerizing AT1 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 AT1 receptor antagonists was used as a new test for the evaluation of the predictive capability of the previously published qualitative and quantitative pharmacophore models.
Read the peer-reviewed publication
affinityindene derivativesstructure optimization1 receptor ligand 6 cmembrane permeabilitypharmacokinetic studies1 Angiotensin II Receptor Antagonists1 receptor affinities1 receptor antagonists1 receptor antagonists 4Binding studiesthermoreversible polymercompounds display1 receptorrelease mechanismpharmacophore models