Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States.
Sterling Pharma Solutions Limited, Sheldon Drive, Cary, North Carolina 27513, United States.
J Med Chem. 2021 Mar 25;64(6):3006-3025. doi: 10.1021/acs.jmedchem.0c01448. Epub 2021 Mar 11.
Apelin receptor agonism improves symptoms of metabolic syndrome. However, endogenous apelin peptides have short half-lives, making their utility as potential drugs limited. Previously, we had identified a novel pyrazole-based agonist scaffold. Systematic modification of this scaffold was performed to produce compounds with improved ADME properties. Compound with favorable agonist potency (cAMPi EC = 162 nM), human liver microsome stability ( = 62 min), and pharmacokinetic profile in rodents was identified. The compound was tested in a mouse model of diet-induced obesity (DIO) and metabolic syndrome for efficacy. Treatment with led to significant weight loss, hypophagia, improved glucose utilization, reduced liver steatosis, and improvement of disease-associated biomarkers. In conclusion, a small-molecule agonist of the apelin receptor has been identified that is suitable for investigation of the apelinergic system in DIO and perhaps other diseases where this receptor has been implicated to play a role.
阿利肽受体激动剂可改善代谢综合征的症状。然而，内源性阿利肽肽的半衰期较短，使其作为潜在药物的应用受到限制。先前，我们已经确定了一种新型的吡唑基激动剂支架。对该支架进行系统修饰，以产生具有改善 ADME 特性的化合物。鉴定出具有有利激动剂效力（cAMPi EC = 162 nM）、人肝微粒体稳定性（ = 62 分钟）和啮齿动物药代动力学特征的化合物 。该化合物在饮食诱导肥胖（DIO）和代谢综合征的小鼠模型中进行了功效测试。用 治疗导致体重显著减轻、食欲减退、葡萄糖利用率提高、肝脂肪变性减少以及与疾病相关的生物标志物改善。总之，已经鉴定出一种阿利肽受体的小分子激动剂，适合用于研究 DIO 中阿利肽能系统，也许还有其他涉及该受体发挥作用的疾病。
