title: QSAR studies on 3-(4-biphenylmethyl) 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] Pyridine derivatives as angiotensin II (AT1) receptor antagonist.
abstract: QSAR studies were performed for correlating the chemical composition of 3-(4-biphenylmethyl) 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] pyridines bearing aryl acetic acid esters and acetamides as angiotensin II AT(1) receptor antagonist. Four different quantitative structure-property relationship (QSAR) methods namely two-dimensional (2D-QSAR), group-based QSAR, k-nearest neighbor and Pharmacophore Modeling were employed to obtain statistically significant models. The statistically significant best 2D-QSAR model having correlation coefficient r(2) = 0:8940 and cross-validated squared correlation coefficient q(2) = 0:7648 with external predictive ability of pred_r(2) = 0:8177,pred_r(2)se = 0.4119 and best group-based QSAR model having r(2) = 0:7392 and q(2) = 0:6710with pred_r(2) = 0:7503was developed by SA-principal component regression. The most predictive k-nearest neighbor model derived from the superposition of conformations has good cross-validated q(2) = 0:7637 and satisfied predictive ability r(2)_pred = 0.7143. Continuing with compounds of substituted 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] pyridine derivatives chemical feature-based pharmacophore models with lowest RMSD value (0.3292 Å) consists of two Hac (Hydrogen bond acceptor), negative ionizable, and two AroC (Aromatic) features are important for the activity. The study suggested that substitution of group at R, R 1, R 2 and Ar, and position on 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] pyridine ring with more electronegative nature and low bulkiness are favorable for the antihypertensive activity. These theoretical results may provide a useful reference for understanding the action mechanism and designing potential angiotensin II (AT1) receptor antagonist.
authors.affiliation: Drug Design and Development Laboratory, School of Pharmacy, Devi Ahilya University, Takshila Campus, Khandwa Road, Indore, 452001, MP, India, mukeshcsharma@yahoo.com.
authors.forename: Mukesh C
authors.initials: MC
authors.lastname: Sharma
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D008958:Models, Molecular; D015233:Models, Statistical; D015394:Molecular Structure; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1