Abstract
| - The 4-phenylquinoline fragment of novel AT1 receptor antagonists 4 based on imidazo[4,5-b]pyridine moietywas replaced by 4-phenylisoquinolinone (compounds 5) or 1-phenylindene (compounds 6) scaffolds toinvestigate the structure−activity relationships. Binding studies showed that most of the synthesizedcompounds display high affinity for the AT1 receptor. Because of the in vitro high potency of carboxylicacids 5b,f, they were evaluated in permeability (in Caco-2 cells) and in pharmacokinetic studies in comparisonwith quinoline derivatives 4b,i,j,k. The studies showed that these compounds are characterized by rapidexcretion, low membrane permeability, and low oral bioavailability. The structure optimization of the indenederivatives led to compounds 6e,f possessing interesting AT1 receptor affinities. Optimization producedpolymerizing AT1 receptor ligand 6c, which forms a thermoreversible polymer (poly-6c) and is releasedfrom the latter by a temperature-dependent kinetics. The results suggest the possibility of developing novelpolymeric prodrugs based on a new release mechanism. Finally, a set of 34 AT1 receptor antagonists wasused as a new test for the evaluation of the predictive capability of the previously published qualitative andquantitative pharmacophore models.
|