Activity landscape analysis, CoMFA and CoMSIA studies of pyrazole CB1 antagonists

Obesity and the metabolic syndrome are pandemic diseases with high morbidity and mortality. With the aim of discovering novel therapies for those diseases, the cannabinoid receptor 1 (CB1), which has been validated as a target for treating appetitive disorders, is now considered a novel target for the design of anti-obesity compounds. Our main goal was to determine the activity landscape of pyrazole derivatives and to develop reliable three-dimensional quantitative structure–activity relationship (3D-QSAR) models. Structure–activity similarity (SAS) maps of pyrazole analogs acting as antagonists of CB1 were constructed in order to identify activity cliffs, compounds that have high structural similarity with the rest of the compound set, but low activity similarity. According to the SAS maps, one molecule was identified as an outlier and before comparative molecular field analysis (COMFA) and comparative molecular similarity analysis (CoMSIA) 3D-QSAR models were derived. The best models resulted in an r ² value of 0.992 and a q ² of 0.766 for CoMFA and an r ² of 0.983 and a q ² of 0.681 for CoMSIA. Contour plots identified that the R³ position at the pyrazole moiety is an important feature for the optimization of the binding affinity to the CB1 receptor. According to our results, these models can be a useful tool for the design and prediction of novel CB1 antagonists.