Bhattacharjee Pinaki, Dvorácskó Szabolcs, Pointeau Océane, Kundu Biswajit, Rutland Nicholas, Puhl Henry, Liu Jie, Godlewski Grzegorz, Hassan Sergio A, Jourdan Tony, Cinar Resat, Iyer Malliga R
Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, MD 20852, USA.
Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, MD 20852, USA; Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, MD 20852, USA.
Metabolism. 2025 Sep;170:156291. doi: 10.1016/j.metabol.2025.156291. Epub 2025 May 12.
The endocannabinoid system is a key regulator of metabolism, sparking interest in cannabinoid type 1 receptor (CB1R) antagonists as potential treatments for obesity and related conditions collectively called metabolic syndrome disorders. However, the neuropsychiatric liabilities associated with centrally acting CB1R antagonists led researchers to focus on developing peripherally restricted compounds that do not cross the blood-brain barrier (BBB). This study aimed to synthesize and evaluate novel CB1R antagonists based on tetrahydropyridazine core incorporating physicochemical design principles that would allow for negligible BBB penetration. The efficacy of the compounds was assessed in rodent models of diet induced obesity and diabetes.
In this study, we employed a rational-design approach along with structure-based modeling to develop small-molecule CB1R antagonists that are peripherally acting. Pharmacological profiles of two racemic compounds PB19A and PB95 were evaluated in cannabinoid receptor binding studies, and functional [S]-GTPγS assays. Further chiral separation of enantiomers allowed for the evaluation of respective eutomers in in vitro ADME studies along with in vivo pharmacokinetic and tissue distribution studies in mice. The results showed that the compounds are orally bioavailable and had negligible brain penetrance. The design features also incorporated putative amidine moieties which inhibit the pro-inflammatory enzyme; inducible nitric oxide synthase (iNOS). Both biochemical and in vitro cell-based assays showed the CB1R antagonists having iNOS inhibitor properties. In vivo CB1R functional antagonism was assessed by upper gastrointestinal motility assay. The efficacy of our CB1R antagonists was compared with brain penetrant ibipinabant in a diet-induced obesity mouse model, assessing effects on lipid metabolism biomarkers, food intake, body weight reduction, glucose tolerance and insulin resistance.
Novel compounds PB19AE2 and PB95E2 were designed and evaluated as peripherally restricted CB1R antagonists. In high fat diet fed mice, these compounds improved metabolic parameters, modestly reduced food intake, and ameliorated hepatic lipid metabolism markers.
Overall, PB19AE2 and PB95E2 are orally bioavailable, peripherally acting CB1 antagonists and their preliminary evaluation show promising potential in utilizing the pyridazine-based compounds for generating potent leads for treating obesity- associated disorders.
内源性大麻素系统是新陈代谢的关键调节因子，这引发了人们对1型大麻素受体（CB1R）拮抗剂作为肥胖及统称为代谢综合征疾病的潜在治疗方法的兴趣。然而，与中枢作用的CB1R拮抗剂相关的神经精神方面的不良反应促使研究人员专注于开发不穿过血脑屏障（BBB）的外周限制型化合物。本研究旨在基于四氢哒嗪核心合成并评估新型CB1R拮抗剂，纳入物理化学设计原则以使BBB穿透可忽略不计。在饮食诱导的肥胖和糖尿病啮齿动物模型中评估了这些化合物的疗效。
在本研究中，我们采用合理设计方法以及基于结构的建模来开发外周作用的小分子CB1R拮抗剂。在大麻素受体结合研究和功能性[S]-GTPγS测定中评估了两种外消旋化合物PB19A和PB95的药理学特征。对映体的进一步手性分离使得能够在体外药物代谢动力学和药物处置研究以及小鼠体内药代动力学和组织分布研究中评估各自的优映体。结果表明这些化合物口服生物利用度良好且脑穿透可忽略不计。设计特征还纳入了假定的脒基部分，其可抑制促炎酶；诱导型一氧化氮合酶（iNOS）。生化和基于体外细胞的测定均表明CB1R拮抗剂具有iNOS抑制特性。通过上消化道运动测定评估体内CB1R功能拮抗作用。在饮食诱导的肥胖小鼠模型中，将我们的CB1R拮抗剂的疗效与可穿透脑的依匹那班进行比较，评估对脂质代谢生物标志物、食物摄入量、体重减轻、葡萄糖耐量和胰岛素抵抗的影响。
设计并评估了新型化合物PB19AE2和PB95E2作为外周限制型CB1R拮抗剂。在高脂饮食喂养的小鼠中，这些化合物改善了代谢参数，适度减少了食物摄入量，并改善了肝脏脂质代谢标志物。
总体而言，PB19AE2和PB95E2是口服生物利用度良好的外周作用CB1拮抗剂，它们的初步评估显示利用基于哒嗪的化合物产生治疗肥胖相关疾病的有效先导物具有广阔前景。
