title: Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists.
abstract: The optimization of the distance between two key pharmacophore features within our first hit compounds 1a and 2a led to the identification of a new class of potent non-peptidic antagonists for the MCH-R1, based around 4-amino-2-cyclohexylaminoquinazolines. In particular, ATC0065 (2c), N2-[cis-4-([2-[4-Bromo-2-(trifluoromethoxy)phenyl]ethyl]amino)cyclohexyl]-N4,N4-dimethylquinazoline-2,4-diamine dihydrochloride, bound with high affinity to the MCH-R1 (IC50 value of 16 nM) and showed good metabolic stability in liver microsomes from human and rat.
authors.affiliation: Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kanuma
authors.forename: Katsunori
authors.initials: K
authors.lastname: Omodera
authors.forename: Mariko
authors.initials: M
authors.lastname: Nishiguchi
authors.forename: Takeo
authors.initials: T
authors.lastname: Funakoshi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Nagase
authors.forename: Izumi
authors.initials: I
authors.lastname: Iida
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Yamaguchi
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Thuy-Anh
authors.initials: TA
authors.lastname: Tran
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sekiguchi
mesh_terms: D000818:Animals; D006801:Humans; D007928:Lethal Dose 50; D008861:Microsomes / Q000378:metabolism; D015394:Molecular Structure; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: C103263:MCHR1 protein, human; D011799:Quinazolines; D017481:Receptors, Somatostatin