Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists.
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.
Kanuma
Kosuke
K
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
Omodera
Katsunori
K
Nishiguchi
Mariko
M
Funakoshi
Takeo
T
Chaki
Shigeyuki
S
Nagase
Yasuko
Y
Iida
Izumi
I
Yamaguchi
Jun-Ichi
J
Semple
Graeme
G
Tran
Thuy-Anh
TA
Sekiguchi
Yoshinori
Y
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*
C103263:MCHR1 protein, human; D011799:Quinazolines; D017481:Receptors, Somatostatin