title: Synthesis and structure-activity relationships of 2-acylamino-4,6-diphenylpyridine derivatives as novel antagonists of GPR54.
abstract: 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.
authors.affiliation: Takeda Pharmaceutical Company, Ltd, Ibaraki 300-4293, Japan. Kobayashi_Toshitake@takeda.co.jp
authors.forename: Toshitake
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Tomita
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukui
authors.forename: Noritaka
authors.initials: N
authors.lastname: Kuroda
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kiba
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takatsu
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohtaki
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Atsuo
authors.initials: A
authors.lastname: Baba
mesh_terms: 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
chemical_list: C118688:KISS1R protein, human; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1