Novel 2 - Alkyl -4 - Biphenyl Sub-methoxy Pyridine At <sub> 1 </ Sub> Receptor Antagonist, The Molecular Design

The quantitative structure-activity relationship (QSAR) of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives was studied. Using three different alignment methods to get the comparative molecular field analysis (CoMFA), the comparative molecular similarity indices analysis (CoMSIA), and the hologram quantitative structure-activity relationship(HQSAR) models, statistical results from the established models showed believable predictivity based on the cross-validated value(q2>0.5) and the non-validated value(r2>0.9). A contour maps analysis of the CoMFA and CoMSIA models showed that the hydrophobic and hydrogen-bond acceptor fileds are important factors that affect the AT1 antagonistic activity of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives except for the steric and electrostatic fields. The structural modification information from different atom contributions in the HQSAR model is in agreement with those of the 3D-QSAR models.According to the bioisostere and the structure modification information from the three best QSAR,1322 new compounds were designed. And their potential activities were predicted with the three best QSAR models,403 compounds with better activity were obtained. Thlose compounds were predicted in their pKa and logP values using LABACD 6.0 and then analyzed in analog dugs using five principles of analog drugs. Those compounds that were consistent with the five principles of analog drugs were put into the Discovery Studio 2.5 to get ADMET analysis. In order to simplify the difficulty of compound synthesis, structures of compounds with good results are simplified according to the best HQSAR model. As a result,47 compounds were gotten to be synthesized.The docking study of the AT1 receptor and ligand couldn't be performed for lacking of the X-ray diffraction structure. In order to explore drug design method based on the structure, homology modeling method were used to get the 3D structure of AT1 receptor. And the homology proteins of AT1 receptor——chemokine receptors (3oedu,3oe6, 3oeO) were used as templates to get sequence alignments. With molecular mechanics and ligand-supported minimization methods, final model IV was obtained. And the Ramachandran plots and Profiles-3D methods were used to assess the model. The result suggests that residues in the binding pocket of the model IV are reasonable in spatial rotation and energy.Docking studies of model IV and ligands were processed. The results of drugs on the market (Candesartan, Valsartan and Eprilsartan), compound 19 in the training set of QSAR models and new compounds suggest that H-bond interations are in line with the literatures.