Discovery of a novel small molecule agonist scaffold for the APJ receptor
Institution:
1. Life Science Research Center, University of South China, Hengyang, Hunan 421001, China;2. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China;3. Department of Orthopedics, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, China;4. Department of Clinical Medicine, Huaihua Medical College, Huaihua, Hunan 418000, China;5. Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada;6. Department of Cardiovascular Medicine, The Second Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
Abstract:
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.
