Cannabinoformins: Designing Biguanide-Embedded, Orally Available, Peripherally Selective Cannabinoid-1 Receptor...

We have designed orally bioavailable, non-brain-penetrant antagonists of the cannabinoid-1 receptor (CB₁R) with a built-in biguanide sensor to mimic 5'-adenosine monophosphate kinase (AMPK) activation for treating obesity-associated co-morbidities. A series of 3,4-diarylpyrazolines bearing rational pharmacophoric pendants designed to limit brain penetration were synthesized and evaluated in CB₁R ligand binding assays and recombinant AMPK assays. The compounds displayed high CB₁R binding affinity and potent CB₁R antagonist activities and acted as AMPK activators. Select compounds showed good oral exposure, with compounds 36, 38-, and 39- showing <5% brain penetrance, attesting to peripheral restriction. In vivo studies of 38- revealed decreased food intake and body weight reduction in diet-induced obese mice as well as oral in vivo efficacy of 38 in ameliorating glucose tolerance and insulin resistance. The designed "cannabinoformin" four-arm CB₁R antagonists could serve as potential leads for treatment of metabolic syndrome disorders with negligible neuropsychiatric side effects.