化学
双胍
安普克
药理学
体内
代谢综合征
大麻素受体
胰岛素抵抗
大麻素
敌手
受体
生物化学
蛋白激酶A
内分泌学
胰岛素
激酶
糖尿病
二甲双胍
医学
生物
生物技术
作者
Szabolcs Dvorácskó,Alexa Herrerias,Alberto Oliverio,Pinaki Bhattacharjee,Lenny Pommerolle,Ziyi Liu,Dechun Feng,Yong Sok Lee,Sergio A. Hassan,Grzegorz Godlewski,Reşat Çınar,Malliga R. Iyer
标识
DOI:10.1021/acs.jmedchem.3c00599
摘要
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-S, and 39-S showing <5% brain penetrance, attesting to peripheral restriction. In vivo studies of 38-S revealed decreased food intake and body weight reduction in diet-induced obese mice as well as oral in vivo efficacy of 38-S 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.
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