title: 2-acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats.
abstract: GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor plays an essential role to modulate sex-hormones including GnRH. Thus, antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis. We recently reported 2-acylamino-4,6-diphenylpyridines as the first small molecule GPR54 antagonists with high potency. However, the representative compound 1 showed low brain exposure, where GPR54 acts as a modulator of gonadotropins by binding with its endogenous ligand, metastin. In order to discover compounds that have not only potent GPR54 antagonistic activity but also good brain permeability, we focused on converting the primary amine on the side chain to a secondary or tertiary amine, and finally we identified 15a containing a piperazine group. This compound exhibited high affinity to human and rat GPR54, apparent antagonistic activity, and high brain exposure. In addition, intravenous administration of 15a to castrated male rat suppressed plasma LH level, which indicates the possibility of a small molecule GPR54 antagonist as a novel drug for sex-hormone dependent diseases.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 10 Wadai, Tsukuba-shi, 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: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kiba
authors.forename: Masami
authors.initials: M
authors.lastname: Kusaka
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Atsuo
authors.initials: A
authors.lastname: Baba
mesh_terms: D000631:Aminopyridines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D018938:Caco-2 Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors / Q000097:blood*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1
chemical_list: D000631:Aminopyridines; C492247:Kiss1r protein, rat; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007986:Luteinizing Hormone