title: Exploring structural requirements for peripherally acting 1,5-diaryl pyrazole-containing cannabinoid 1 receptor antagonists for the treatment of obesity.
abstract: Peripherally acting cannabinoid 1 (CB1) receptor antagonists are considered as potential therapeutics for the treatment of obesity with desired efficacy and reduced central nervous system side effects. A dataset of 72 compounds containing the 1,5-diaryl pyrazole basic skeleton having peripheral CB1 receptor antagonistic activity was utilized for three-dimensional quantitative structure-activity relationship studies. Compounds of the series exhibited high variations in the biological activity and chemical structures. Different types of molecular alignments, such as atom-based, data-based, centroid-based and centroid/atom-based were utilized to develop the best CoMFA model. The best CoMFA model was obtained with a database alignment and the same alignment was further used for the development of a CoMSIA model. The best developed CoMFA model had [Formula: see text] with six components, [Formula: see text] while the best developed CoMSIA model had [Formula: see text] with six components, [Formula: see text] and [Formula: see text] The predictive [Formula: see text] values of these two models showed test set predictions of 0.528 and 0.679 for the best CoMFA and CoMSIA models, respectively. Based on a higher [Formula: see text] value, the CoMSIA model was found to be the best one. The prediction accuracy and reliability of the best developed CoMSIA model have been validated using well-established methods. Using the inputs from the best CoMSIA contour maps, several novel highly selective peripherally acting CB1 receptor antagonists have been designed and reported herein.
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara, 390 001, India.
authors.forename: Mayank Kumar
authors.initials: MK
authors.lastname: Sharma
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara, 390 001, India.
authors.forename: Prashant R
authors.initials: PR
authors.lastname: Murumkar
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara, 390 001, India.
authors.forename: Rajani
authors.initials: R
authors.lastname: Giridhar
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara, 390 001, India. mryadav11@yahoo.co.in.
authors.forename: Mange Ram
authors.initials: MR
authors.lastname: Yadav
mesh_terms: D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*
chemical_list: D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1
keywords: 1, 5-Diaryl pyrazole; 3D-QSAR; CB1 receptor antagonists; Endocannabinoids; Rimonabant