Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
Center for Pulmonary Vascular Disease, Duke University Medical Center, Durham, NC 27710, United States.
Bioorg Med Chem. 2020 Feb 15;28(4):115237. doi: 10.1016/j.bmc.2019.115237. Epub 2019 Nov 30.
The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly attractive target for pulmonary and cardiometabolic diseases. Small molecule regulators of this receptor with good drug-like properties are needed. Recently, we discovered a novel pyrazole based small molecule agonist 8 of the apelin receptor (EC = 21.5 µM, K = 5.2 µM) through focused screening which was further optimized to initial lead 9 (EC = 0.800 µM, K = 1.3 µM). In our efforts to synthesize more potent agonists and to explore the structural features important for apelin receptor agonism, we carried out structural modifications at N1 of the pyrazole core as well as the amino acid side-chain of 9. Systematic modifications at these two positions provided potent small molecule agonists exhibiting EC values of <100 nM. Recruitment of β-arrestin as a measure of desensitization potential of select compounds was also investigated. Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β-arrestin recruitment. These compounds may be suitable as tools for in vivo studies of apelin receptor function.
阿皮林能系统由阿皮林受体及其同源阿皮林和伊拉贝拉肽配体组成，具有不同的长度。该系统已成为肺部和心脏代谢疾病越来越有吸引力的靶点。需要具有良好成药性的该受体的小分子调节剂。最近，我们通过有针对性的筛选发现了一种新型的基于吡唑的阿皮林受体小分子激动剂 8（EC=21.5µM，K=5.2µM），并进一步优化为初始先导化合物 9（EC=0.800µM，K=1.3µM）。在我们努力合成更有效的激动剂并探索对阿皮林受体激动作用很重要的结构特征时，我们对吡唑核心的 N1 以及 9 的氨基酸侧链进行了结构修饰。这两个位置的系统修饰提供了具有 EC 值<100nM 的有效小分子激动剂。还研究了选择化合物的β-抑制蛋白募集作为脱敏潜力的衡量标准。几种化合物具有功能选择性，偏向于钙动员而不是β-抑制蛋白募集。这些化合物可能适合作为体内阿皮林受体功能研究的工具。
