Quantitative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 1,4-dihydropyridines and pyridines as multidrug resistance modulators

Purpose. The aim of this study was to develop quantitative structure-activity/pharmacokinetic relationships (QSAR/QSPKR) for a series of synthesized 1,4-dihydropyridines (DHPs) and pyridines as P-glycoprotein (P-gp) inhibitors. Methods. Molecular descriptors of test compounds were generated by 3D molecular modeling using SYBYL and KowWin programs. Forward inclusion coupled with multiple linear regression (MLR) was used to derive a QSAR equation for Ca²⁺ channel binding. A multivariate statistical technique, partial least square (PLS) regression, was applied to derive a QSAR model for P-gp inhibition and QSPKR models. Cross-validation using the "leave-one- out" method was performed to evaluate the predictive performance of models. Results. For Ca²⁺ channel binding, the MLR equation indicated a good correlation between observed and predicted values (R ² = 0.90), and cross-validation confirmed the predictive ability of the model (Q ² = 0.67). For P-gp reversal, the model obtained by PLS could account for most of the variation in P-gp inhibition (R ² = 0.76) with fair predictive performance (Q ² = 0.62). Nine structurally related 1,4-DHP drugs were used for QSPKR analysis. The models could explain the majority of the variation in clearance (R ² = 0.90), and cross-validation confirmed the prediction ability (Q ² = 0.69). Conclusion. QSAR/QSPKR models were developed, and the QSAR models were capable of identifying synthesized 1,4-DHPs and pyridines with potent P-gp inhibition and reduced Ca²⁺ channel binding. The QSPKR models provide insight into the contribution of electronic, steric, and lipophilic factors to the clearance of DHPs.