Derivation of pharmacophore and CoMFA models for leukotriene D(4) receptor antagonists of the quinolinyl(bridged)aryl series.

Abstract

The present work focuses on the study of the three-dimensional (3D) structural requirements for the leukotriene D(4) (LTD(4)) antagonistic activity of compounds having the basic quinolinyl(bridged)aryl framework. An approach combining pharmacophore mapping, molecule alignment, and CoMFA models was used to derive a hypothesis for a series of LTD(4) antagonists having the basic diaryl-bridged framework. In this compound series, the produced pharmacophore hypotheses have shown to yield molecule alignments suitable to derive valuable CoMFA models. Model selection focused on (1) obtention of coherent modeling results, (2) consistency with the available SAR data, and (3) ability to predict the activity of an independent set of congeneric molecules. This approach resulted in a combined pharmacophore and CoMFA model that can generally represent the antagonistic activity within a log unit of the measured value for compounds of the series. The resulting pharmacophore (model C) consists of an acidic or negative ionizable function (AC), a hydrogen-bond acceptor (HBA), and three hydrophobic regions (HY) and produces chemically meaningful alignments with the most active compounds of the series mapping the pharmacophore in a extended energetically favorable conformation.