Synthesis and structure–activity relationships of 2-acylamino-4,6-diphenylpyridine derivatives as novel antagonists of GPR54 Original Research Article

GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor has an essential role to modulate sex-hormones including GnRH. Though antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis, small molecule GPR54 antagonists have not been reported. We have synthesized a series of 2-acylamino-4,6-diphenylpyridines to identify potent GPR54 antagonists. Detailed structure–activity relationship studies led to compound 9l with an IC50 value of 3.7 nM in a GPR54 binding assay, and apparent antagonistic activity in a cellular functional assay.