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

The present work focuses on the study of the three-dimensional (3D) structu ral requirements for the leukotriene D-4 (LTD4) antagonistic activity of co mpounds having the basic quinolinyl-(bridged)aryl framework. An approach co mbining pharmacophore mapping, molecule alignment, and CoMFA models was use d to derive a hypothesis for a series of LTD4 antagonists having the basic diaryl-bridged framework. In this compound series, the produced pharmacopho re hypotheses have shown to yield molecule alignments suitable to derive va luable CoMFA models. Model selection focused on (1) obtention of coherent m odeling results, (2) consistency with the available SAR data, and (3) abili ty to predict the activity of an independent set of congeneric molecules. T his approach resulted in a combined pharmacophore and CoMFA model that can generally represent the antagonistic activity within a log unit of the meas ured value for compounds of the series. The resulting pharmacophore (model C) consists of an acidic or negative ionizable function (AC), a hydrogen-bo nd acceptor (HBA), and three hydrophobic regions (HY) and produces chemical ly meaningful alignments with the most active compounds of the series mappi ng the pharmacophore in a extended energetically favorable conformation.