Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1.
The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride 28 (ATC0175), which showed excellent antagonist activity at the MCH-R1 (IC50 = 3.4 nM) as well as good selectivity over the Y5 and the alpha2A receptors.
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
Semple
Graeme
G
Tran
Thuy-Anh
TA
Kramer
Bryan
B
Hsu
Debbie
D
Casper
Martin
M
Thomsen
Bill
B
Sekiguchi
Yoshinori
Y
D006801:Humans; D020128:Inhibitory Concentration 50; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C103263:MCHR1 protein, human; D011799:Quinazolines; D017481:Receptors, Somatostatin