Pyrazole Agonist of the Apelin Receptor Improves Symptoms of Metabolic Syndrome in Mice

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 13 with favorable agonist potency
(cAMPi EC50 = 162 nM), human liver microsome stability
(T1/2 = 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 13 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 in vivo investigation of the apelinergic system
in DIO and perhaps other diseases where this receptor has been implicated
to play a role.

Apelin受体（Apelin receptor）激动作用可改善代谢综合征（metabolic syndrome）相关症状。然而，内源性Apelin肽的半衰期较短，使其作为潜在治疗药物的应用潜力受到限制。此前，本课题组已鉴定得到一种新型基于吡唑的激动剂骨架（pyrazole-based agonist scaffold）。针对该骨架开展系统性修饰，以获得ADME特性（ADME properties）更为优异的目标化合物。最终筛选得到化合物13，其具备优异的激动剂活性（cAMPi EC50=162 nM）、良好的人肝微粒体稳定性（半衰期T1/2=62 min），且在啮齿类动物体内具有理想的药代动力学特征（pharmacokinetic profile）。随后，该化合物在饮食诱导肥胖（DIO）及代谢综合征小鼠模型中开展药效学评价。结果显示，化合物13给药可显著减轻小鼠体重、减少摄食、改善葡萄糖利用能力、缓解肝脏脂肪变性，并改善疾病相关生物标志物水平。综上，本研究成功鉴定得到一种Apelin受体小分子激动剂，其可用于在饮食诱导肥胖（DIO）及其他可能涉及该受体发挥病理生理作用的疾病中，开展Apelin能系统（apelinergic system）的体内研究。