Discovery of pyrazine carboxamide CB1 antagonists: the introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series.
Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose.
Ellsworth
Bruce A
BA
Pharmaceutical Research Institute, Bristol Myers Squibb Co., PO Box 5400 Princeton, NJ 08543, USA. Bruce.Ellsworth@bms.com
Wang
Ying
Y
Zhu
Yeheng
Y
Pendri
Annapurna
A
Gerritz
Samuel W
SW
Sun
Chongqing
C
Carlson
Kenneth E
KE
Kang
Liya
L
Baska
Rose A
RA
Yang
Yifan
Y
Huang
Qi
Q
Burford
Neil T
NT
Cullen
Mary Jane
MJ
Johnghar
Susan
S
Behnia
Kamelia
K
Pelleymounter
Mary Ann
MA
Washburn
William N
WN
Ewing
William R
WR
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000577:Amides; D043884:Receptor, Cannabinoid, CB1; D011718:Pyrazinamide; C005296:pyrazinoic acid