Aminopyrazine CB1 receptor inverse agonists.
A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.
Wustrow
David J
DJ
Neurogen Corporation, 35 Northeast Industrial Road, Branford CT 06405, USA. dwustrow@nrgn.com
Maynard
George D
GD
Yuan
Jun
J
Zhao
He
H
Mao
Jianmin
J
Guo
Qin
Q
Kershaw
Mark
M
Hammer
Jack
J
Brodbeck
Robbin M
RM
Near
Kristen E
KE
Zhou
Dan
D
Beers
David S
DS
Chenard
Bertrand L
BL
Krause
James E
JE
Hutchison
Alan J
AJ
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D020650:Combinatorial Chemistry Techniques; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D009765:Obesity / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011719:Pyrazines / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000097:blood; D000077285:Rimonabant; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D065692:Cytochrome P-450 CYP3A Inhibitors; D010880:Piperidines; D011719:Pyrazines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077285:Rimonabant