Synthesis, Biological Evaluation, and Molecular Modeling Studies of 3,4-Diarylpyrazoline Series of Compounds as Potent, Nonbrain Penetrant Antagonists of Cannabinoid-1 (CB1R) Receptor with Reduced Lipophilicity.

Abstract

In the present report, we describe the synthesis and structure-activity relationships of novel "four-arm" dihydropyrazoline compounds designed as peripherally restricted antagonists of cannabinoid-1 receptor (CB1R). A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB1 receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, showed high affinity for CB1R and potent in vitro CB1R antagonist activities. Promising compounds with potent CB1R activity were evaluated in tissue distribution studies. Compounds 6a, 6f, and 7c showed limited brain penetrance attesting to its peripheral restriction. The 4S-enantiomer of these compounds further showed a stereoselective affinity for the CB1 receptor and behaved as inverse agonists. In vivo studies on food intake and body weight reduction in diet-induced obese (DIO) mice showed that these compounds could serve as potential leads for the development of selective CB1R antagonists with improved potency and peripheral restriction.