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

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 (CBR). A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, showed high affinity for CBR and potent CBR antagonist activities. Promising compounds with potent CBR activity were evaluated in tissue distribution studies. Compounds , , and showed limited brain penetrance attesting to its peripheral restriction. The 4-enantiomer of these compounds further showed a stereoselective affinity for the CB receptor and behaved as inverse agonists. 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 CBR antagonists with improved potency and peripheral restriction.