Cholesteryl ester transfer protein (CETP) is involved in trafficking lipoprotein 
particles and neutral lipids between HDL and LDL and therefore is considered a 
valid target for treating dyslipidemic conditions and complications. 
Pharmacophore modeling and quantitative structure-activity relationship (QSAR) 
analysis were combined to explore the structural requirements for potent CETP 
inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r(2)=0.800, 
n=96, F=72.1, r(2)(LOO) =0.775, r(2)(PRESS) against 22 external test 
inhibitors=0.707) suggesting the existence of at least two distinct binding 
modes accessible to ligands within CETP binding pocket. The successful 
pharmacophores were complemented with strict shape constraints in an attempt to 
optimize their receiver-operating characteristic (ROC) curve profiles. The 
validity of our modeling approach was experimentally established by the 
identification of several CETP inhibitory leads retrieved via in silico 
screening of the National Cancer Institute (NCI) list of compounds and an in 
house built database of drugs and agrochemicals. Two hits illustrated low 
micromolar IC(50) values: NSC 40331 (IC(50)=6.5 microM) and NSC 89508 
(IC(50)=1.9 microM). Active hits were then used to guide synthetic exploration 
of a new series of CETP inhibitors.