Synthesis and structure-activity relationships of 2-acylamino-4,6-diphenylpyridine derivatives as novel antagonists of GPR54.

Bioorganic & medicinal chemistry 2010 Apr 20; In press

Kobayashi T, Sasaki S, Tomita N, Fukui S, Kuroda N, Nakayama M, Kiba A, Takatsu Y, Ohtaki T, Itoh F, Baba A

Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 10 Wadai, Tsukuba-shi, Ibaraki 300-4293, Japan.

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 IC(50) value of 3.7nM in a GPR54 binding assay, and apparent antagonistic activity in a cellular functional assay.

Keywords: GPR54 prostate cancer endometriosis