APJ receptor agonism for metabolic syndrome

本项目的总体目标是开发apelin（APJ）受体激动剂来治疗饮食诱导的肥胖 (DIO)和相关的代谢综合征。代谢综合征可导致几种危及生命的疾病 包括高血压、心脏病、II型糖尿病、脂肪性肝炎、中风和某些类型的癌症。 现有的治疗肥胖症的药物有严重的副作用和有限的疗效。因此，新的药物 围绕新的目标。APJ受体是一种G蛋白偶联受体（GPCR）蛋白， 由爱帕琳肽和新描述的称为TODDLER/ELABELA的激素激活。是新兴 需要药理学验证的代谢综合征的多模式目标。爱帕琳是一种胰岛素 促进脂肪酸氧化的敏化剂。爱帕琳基因敲除（ko）小鼠具有更高的胰岛素水平和葡萄糖 不耐受沿着腹部脂肪增加和体重增加。Apelin通过与APJ的相互作用 可以抑制前脂肪细胞的成熟和成熟脂肪细胞中的脂解。apelin激活APJ 内皮导致形成大的、无渗漏的淋巴管和血管，限制了运输 脂肪酸及其在脂肪中的摄取与这些数据一致，apelin ko小鼠的血管比其他小鼠的血管更长， 适合FA运输。另一份报告表明，爱帕琳转基因小鼠通过以下途径对DIO具有抗性： 由于骨骼肌中血管质量和线粒体生物发生增加。这种非肽探针 没有适合于体内工作的受体。我们已经确定了一种结构新颖的激动剂支架， 通过高通量筛选进一步发展。我们建议改进我们早期的铅化合物， 使用三个迭代特定目标生成APJ的体内探针。通过目标1，综合和完善 APJ探测将继续使用药物化学方法。通过目标2，这些化合物将 使用功能性和放射性配体置换试验对APJ地区进行了表征。有效的化合物将在 使用一组ADMET和药代动力学测定表征。通过aim 3，在体内测试的最佳 化合物将在啮齿动物的慢性DIO模型中进行。建成后将 验证APJ地区作为治疗代谢综合征药物开发的目标， 为最终的临床开发生产先进的先导化合物。

The overall goal of this project is to develop apelin (APJ) receptor agonists to treat diet-induced obesity (DIO) and related metabolic syndrome. Metabolic syndrome can lead to several life threatening conditions including hypertension, heart disease, type II diabetes, steatohepatitis, stroke, and certain types of cancer. Available medications to treat obesity have serious side effects and limited efficacy. Thus, new medications around novel targets are needed. The APJ receptor is a G-protein coupled receptor (GPCR) protein that is activated by apelin peptides and a newly described hormone called TODDLER/ELABELA. It is an emerging multi-modal target for metabolic syndrome that needs pharmacological validation. Apelin is an insulin sensitizer that promotes fatty acid oxidation. Apelin knockout (ko) mice have higher insulin levels and glucose intolerance along with increased abdominal fat and higher bodyweight. Apelin through its interaction with APJ can inhibit maturation of pre-adipocytes and lipolysis in mature adipocytes. Activation of APJ by apelin in the endothelium leads to the formation of large, non-leaky lymphatic and blood vessels that restrict the transport of FA and their uptake in adipose. In agreement with these data, apelin ko mice have vessels that are more amenable to FA transport. Another report has indicated that apelin transgenic mice are resistant to DIO by virtue of increased vascular mass and mitochondrial biogenesis in skeletal muscles. Non-peptide probes of this receptor suitable for in vivo work are not available. We have identified a structurally novel agonist scaffold for further development through high-throughput screening. We propose to refine our early lead compounds to produce in vivo probes of APJ using three iterative specific aims. Through aim 1, synthesis and refinement of APJ probes will continue using medicinal chemistry approaches. Through aim 2, these compounds will be characterized using functional and radioligand displacement assays for APJ. Potent compounds will be then characterized using a battery of ADMET and pharmacokinetic assays. Through aim 3, in vivo testing of the best compounds will be performed in a chronic model of DIO in rodents. Completion of the project will pharmacologically validate APJ as a target for medications development to treat metabolic syndrome and produce advanced lead compounds for eventual clinical development.