Discovery of a novel small molecule agonist scaffold for the APJ receptor.
Discovery of a novel small molecule agonist scaffold for the APJ receptor.
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DOI：
10.1016/j.bmc.2016.06.018
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发表时间：
2016-08-15
影响因子：
3.5
通讯作者：
Runyon SP
中科院分区：
文献类型：
--
作者：
Narayanan S;Maitra R;Deschamps JR;Bortoff K;Thomas JB;Zhang Y;Warner K;Vasukuttan V;Decker A;Runyon SP
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.
