CP-800569

Quantitative structure–activity relationships have been developed for a set of 40 halogenated substituted N‐benzyl‐N‐phenyl aminoalcohol compounds. IC50 values for Cholesteryl Ester Transfer Protein (CETP) inhibition activity for these compounds expressed in log units have been modeled by Multiple Linear Regression Analysis (MLRA) based on descriptors generated by DRAGON software and optimal descriptors approach. Forty benzene derivatives have been divided into training (n=20) and test (n=20) sets. In the case of the MLRA, the three‐variable model has the best predictive potential. Comparison of the quality of MLRA and optimal descriptor models shows that the predictive potential of the one‐variable model, based on the optimal descriptor, provides a low correlation coefficient in the training set. However, this one‐variable model performs better for the test set when compared to the two‐ and three‐variable MLRA models.

A three dimensional-quant. structure activity relationship (3D-QSAR) study was performed on a series of CETP inhibitors N,N-disubstituted trifluoro-3-amino-2-propanol derivatives using VolSurf descriptors and the comparative mol. field anal. (CoMFA) method.Good results were obtained and the training set was predictable for the test set.VolSurf descriptor anal. showed that suitable hydrophilicity, more hydrogen bond donors and less acceptor were favorable to activity.To some extent, high mol. weight, a smooth surface and high non-globularity were also beneficial to activity.High hydrophobicity and an imbalance between the center of mass and the barycenter of its hydrophobic regions decreased the activity.The result of CoMFA demonstrated that the activity was influenced more by steric effect than electrostatic effect.At the phenoxy meta position in the N-Ph substituent, groups that have a large volume and strong pos. electricity increase the activity.At the meta position of the N-benzyl substituent, groups that have a large volume and suitable electronegativity were beneficial to activity.At the para position of the benzyl group, a large steric effect was detrimental to activity.VolSurf descriptors provided the integral property information of the mols. and CoMFA gave information on substituents.Both methods complemented each other, which can provide assistance to the design of new compounds belonging to this class of inhibitors.