title: Discovery, synthesis, and structure-activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists.
abstract: Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4'-fluoro-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi, 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan. Kamata_Makoto@takeda.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamata
authors.forename: Toshiro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Imaeda
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
authors.forename: Jun
authors.initials: J
authors.lastname: Terauchi
authors.forename: Maki
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Taiichi
authors.initials: T
authors.lastname: Ora
authors.forename: Michiko
authors.initials: M
authors.lastname: Tawada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Shiro
authors.initials: S
authors.lastname: Takekawa
authors.forename: Asano
authors.initials: A
authors.lastname: Asami
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Nagisa
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakano
authors.forename: Kaoru
authors.initials: K
authors.lastname: Watanabe
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ogino
authors.forename: Koki
authors.initials: K
authors.lastname: Kato
authors.forename: Kaneyoshi
authors.initials: K
authors.lastname: Kato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008820:Mice, Obese; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008024:Ligands; C103263:MCHR1 protein, human; C491208:MCHR1 protein, rat; D017481:Receptors, Somatostatin; D013764:Tetrahydronaphthalenes