Exploring structural requirements for peripherally acting 1,5-diaryl pyrazole-containing cannabinoid 1 receptor antagonists for the treatment of obesity

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 presented.) = 0.552 with six components, (Formula presented.) = 0.973, standard error of estimate =0.162,F-value = 281.239, while the best developed CoMSIA model had (Formula presented.) = 0.571 with six components, (Formula presented) = 0.960, standard error of estimate = 0.196 and F-value = 188.701. The predictive r 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 presented.) 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.