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.
Semple
Graeme
G
Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. gsemple@arenapharm.com
Tran
Thuy-Anh
TA
Kramer
Bryan
B
Hsu
Debbie
D
Han
Sangdon
S
Choi
Juyi
J
Vallar
Pureza
P
Casper
Martin D
MD
Zou
Ning
N
Hauser
Erin K
EK
Thomsen
William
W
Whelan
Kevin
K
Sengupta
Dipanjan
D
Morgan
Michael
M
Sekiguchi
Yoshinori
Y
Kanuma
Kosuke
K
Chaki
Shigeyuki
S
Grottick
Andrew J
AJ
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