Khan Nayaab, Laudermilk Lucas, Ware Jalen, Rosa Taylor, Mathews Kelly, Gay Elaine, Amato George, Maitra Rangan
Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States.
ACS Pharmacol Transl Sci. 2021 Mar 9;4(2):757-764. doi: 10.1021/acsptsci.0c00213. eCollection 2021 Apr 9.
Metabolic syndrome (MetS) is a complex disorder that stems from the additive effects of multiple underlying causes such as obesity, insulin resistance, and chronic low-grade inflammation. The endocannabinoid system plays a central role in appetite regulation, energy balance, lipid metabolism, insulin sensitivity, and β-cell function. The type 1 cannabinoid receptor (CB1R) antagonist SR141716A (rimonabant) showed promising antiobesity effects, but its use was discontinued due to adverse psychiatric events in some users. These adverse effects are due to antagonism of CB1R in the central nervous system (CNS). As such, CNS-sparing CB1R antagonists are presently being developed for various indications. In this study, we report that a recently described compound, 3-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9-purin-6-yl]piperidin-4-yl}-1-[6-(difluoromethoxy)pyridin-3-yl]urea (RTI1092769), a pyrazole based weak inverse agonist/antagonist of CB1 with very limited brain exposure, improves MetS related complications. Treatment with RTI1092769 inhibited weight gain and improved glucose utilization in obese mice maintained on a high fat diet. Hepatic triglyceride content and steatosis significantly improved with treatment. These phenotypes were supported by improvement in several biomarkers associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). These results reinforce the idea that CB1 antagonists with limited brain exposure should be pursued for MetS and other important indications.
代谢综合征（MetS）是一种复杂的病症，源于肥胖、胰岛素抵抗和慢性低度炎症等多种潜在病因的叠加效应。内源性大麻素系统在食欲调节、能量平衡、脂质代谢、胰岛素敏感性和β细胞功能中起核心作用。1型大麻素受体（CB1R）拮抗剂SR141716A（利莫那班）显示出有前景的抗肥胖作用，但由于一些使用者出现不良精神事件而停止使用。这些不良反应是由于中枢神经系统（CNS）中CB1R的拮抗作用。因此，目前正在开发对中枢神经系统有保护作用的CB1R拮抗剂用于各种适应症。在本研究中，我们报告了一种最近描述的化合物，3-{1-[8-(2-氯苯基)-9-(4-氯苯基)-9-嘌呤-6-基]哌啶-4-基}-1-[6-(二氟甲氧基)吡啶-3-基]脲（RTI1092769），一种基于吡唑的CB1弱反向激动剂/拮抗剂，其在脑中的暴露非常有限，可改善与代谢综合征相关的并发症。用RTI1092769治疗可抑制高脂饮食喂养的肥胖小鼠体重增加并改善葡萄糖利用。治疗后肝脏甘油三酯含量和脂肪变性显著改善。这些表型得到了与非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）相关的几种生物标志物改善的支持。这些结果强化了这样一种观点，即对于代谢综合征和其他重要适应症，应寻求脑暴露有限的CB1拮抗剂。
