title: Aminopyrazine CB1 receptor inverse agonists.
abstract: 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.
authors.affiliation: Neurogen Corporation, 35 Northeast Industrial Road, Branford CT 06405, USA. dwustrow@nrgn.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Wustrow
authors.forename: George D
authors.initials: GD
authors.lastname: Maynard
authors.forename: Jun
authors.initials: J
authors.lastname: Yuan
authors.forename: He
authors.initials: H
authors.lastname: Zhao
authors.forename: Jianmin
authors.initials: J
authors.lastname: Mao
authors.forename: Qin
authors.initials: Q
authors.lastname: Guo
authors.forename: Mark
authors.initials: M
authors.lastname: Kershaw
authors.forename: Jack
authors.initials: J
authors.lastname: Hammer
authors.forename: Robbin M
authors.initials: RM
authors.lastname: Brodbeck
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Near
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: David S
authors.initials: DS
authors.lastname: Beers
authors.forename: Bertrand L
authors.initials: BL
authors.lastname: Chenard
authors.forename: James E
authors.initials: JE
authors.lastname: Krause
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Hutchison
mesh_terms: 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
chemical_list: 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