Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: in vitro profiling and in vivo evaluation.
A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. gsemple@arenapharm.com
Graeme
G
Semple
Thuy-Anh
TA
Tran
Bryan
B
Kramer
Debbie
D
Hsu
Sangdon
S
Han
Juyi
J
Choi
Pureza
P
Vallar
Martin D
MD
Casper
Ning
N
Zou
Erin K
EK
Hauser
William
W
Thomsen
Kevin
K
Whelan
Dipanjan
D
Sengupta
Michael
M
Morgan
Yoshinori
Y
Sekiguchi
Kosuke
K
Kanuma
Shigeyuki
S
Chaki
Andrew J
AJ
Grottick
D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D003514:Cyclohexylamines / Q000737:chemistry*; D004435:Eating; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011799:Quinazolines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015431:Weight Loss
D019440:Anti-Obesity Agents; D003514:Cyclohexylamines; C103263:MCHR1 protein, human; C501654:N-(4-((4-(dimethylamino)quinazolin-2-yl)amino)cyclohexyl)-3,4-difluorobenzamide; D011743:Pyrimidines; D011799:Quinazolines; D017481:Receptors, Somatostatin