Cholesteryl ester transfer protein inhibitors in coronary heart disease: Validated comparative QSAR modeling of N, N-disubstituted trifluoro-3-amino-2-propanols

Abstract

Cholesteryl ester transfer protein (CETP) converts high density lipoprotein cholesterol to low density lipoproteins. It is a promising target for treatment of coronary heart disease. Two dimensional quantitative structure activity relationship (2D-QSAR), hologram QSAR (HQSAR) studies and comparative molecular field analysis (CoMFA) as well as comparative molecular similarity analysis (CoMSIA) were performed on 104 CETP inhibitors. The statistical qualities of generated models were justified by internal and external validation, i.e., q2 and R2pred respectively. The best 2D-QSAR model was obtained with q2 and R2pred values of 0.794 and 0.796 respectively. The 2D-QSAR study suggests that unsaturation, branching and van der Waals volumes may play important roles. The HQSAR model showed q2 and R2pred values of 0.628 and 0.550 respectively. Similarly, CoMFA model showed q2 and R2pred values of 0.707 and 0.755 respectively whereas CoMSIA model was obtained with q2 and R2pred values of 0.696 and 0.703 respectively. CoMFA and CoMSIA studies indicate that steric factors are important at substituted phenoxy and tetrafluoroethoxy groups whereas electropositive factors play important role at difluoromethyl group. The results of 3D-QSAR studies validate those of 2D-QSAR and HQSAR studies as well as the earlier observed SAR data. Current work may help to develop better CETP inhibitors.