Synthesis and structure-activity relationships of 2-acylamino-4,6-diphenylpyridine derivatives as novel antagonists of GPR54.
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.
Kobayashi
Toshitake
T
Takeda Pharmaceutical Company, Ltd, Ibaraki 300-4293, Japan. Kobayashi_Toshitake@takeda.co.jp
Sasaki
Satoshi
S
Tomita
Naoki
N
Fukui
Seiji
S
Kuroda
Noritaka
N
Nakayama
Masaharu
M
Kiba
Atsushi
A
Takatsu
Yoshihiro
Y
Ohtaki
Tetsuya
T
Itoh
Fumio
F
Baba
Atsuo
A
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D020128:Inhibitory Concentration 50; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D000074502:Receptors, Kisspeptin-1; D013329:Structure-Activity Relationship
C118688:KISS1R protein, human; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1