APJ receptor agonism for metabolic syndrome

该项目的总体目标是开发apelin(Apj)受体激动剂来治疗饮食引起的肥胖。 (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情况 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副作用严重，疗效有限。因此，新的药物 围绕新的目标是需要的。APJ受体是一种G蛋白偶联受体(GPCR)蛋白，它是 由apelin多肽和一种新描述的名为toddler/ELABELA的激素激活。它是一种新兴的 需要药理学验证的代谢综合征的多模式靶点。阿佩林是一种胰岛素 促进脂肪酸氧化的增敏剂。Apelin基因敲除(Ko)小鼠的胰岛素水平和血糖水平较高 不耐受伴随腹部脂肪增加和体重增加。Apelin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的脂肪分解。Apelin对APJ的激活作用 内皮导致大的、无渗漏的淋巴管和血管的形成，从而限制运输。 脂肪酸及其在脂肪中的摄取。与这些数据一致的是，apelin ko小鼠的血管比 适用于FA运输。另一份报告表明，apelin转基因小鼠通过以下方式抵抗DIO 骨骼肌中血管质量增加和线粒体生物发生的优点。非肽探针对此的研究 目前还没有适合体内工作的受体。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。我们建议将我们早期的先导化合物提炼成 使用三个迭代的特定目标制作APJ的活体探针。通过目标1，合成和提炼 APJ探测器将继续使用药物化学方法。通过AIM 2，这些化合物将被 用APJ的官能团和放射性配体置换分析进行了表征。强效化合物将会是 使用一系列ADMET和药代动力学分析进行表征。通过AIM 3，体内最好的测试 化合物将在啮齿类动物的慢性DIO模型中进行。该项目的完成将 从药理学角度验证APJ作为治疗代谢综合征和 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.