化学
兴奋剂
阿佩林
受体
部分激动剂
功能选择性
药理学
内源性激动剂
药物发现
G蛋白偶联受体
效力
体外
生物化学
生物
多巴胺受体D1
作者
Sanju Narayanan,Rangan Maitra,Jeffrey R. Deschamps,Katherine Bortoff,James B. Thomas,Yanyan Zhang,Keith R. Warner,Vineetha Vasukuttan,Ann M. Decker,Scott P. Runyon
标识
DOI:10.1016/j.bmc.2016.06.018
摘要
The apelinergic system includes a series of endogenous peptides apelin, ELABELA/TODDLER and their 7-transmembrane G-protein coupled apelin receptor (APJ, AGTRL-1, APLNR). The APJ receptor is an attractive therapeutic target because of its involvement in cardiovascular diseases and potentially other disorders including liver fibrosis, obesity, diabetes, and neuroprotection. To date, pharmacological characterization of the APJ receptor has been limited due to the lack of small molecule functional agonists or antagonists. Through focused screening we identified a drug-like small molecule agonist hit 1 with a functional EC50 value of 21.5 ± 5 μM and binding affinity (Ki) of 5.2 ± 0.5 μM. Initial structure–activity studies afforded compound 22 having a 27-fold enhancement in potency and the first sub-micromolar full agonist with an EC50 value of 800 ± 0.1 nM and Ki of 1.3 ± 0.3 μM. Preliminary SAR, synthetic methodology, and in vitro pharmacological characterization indicate this scaffold will serve as a favorable starting point for further refinement of APJ potency and selectivity. Download : Download full-size image
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