New bicyclic cannabinoid receptor-1 (CB1-R) antagonists.
A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB(1)-R antagonists and inverse agonists. Optimization of the structure-activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in a loss of binding affinity.
Carpino
Philip A
PA
Pfizer Global Research and Development-Groton Laboratories, Groton, CT 06340, USA. philip.a.carpino@pfizer.com
Griffith
David A
DA
Sakya
Subas
S
Dow
Robert L
RL
Black
Shawn C
SC
Hadcock
John R
JR
Iredale
Philip A
PA
Scott
Dennis O
DO
Fichtner
Michael W
MW
Rose
Colin R
CR
Day
Robert
R
Dibrino
Joseph
J
Butler
Mary
M
Debartolo
Demetria B
DB
Dutcher
Darrin
D
Gautreau
Denise
D
Lizano
Jeff S
JS
O'connor
Rebecca E
RE
Sands
Michelle A
MA
Kelly-Sullivan
Dawn
D
Ward
Karen M
KM
D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D008954:Models, Biological; D010880:Piperidines / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D047069:Pyrazolones / Q000737:chemistry; D011744:Pyrimidinones / Q000737:chemistry; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D012377:Rodentia; D013329:Structure-Activity Relationship
D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010880:Piperidines; D011720:Pyrazoles; D047069:Pyrazolones; D011744:Pyrimidinones; D043884:Receptor, Cannabinoid, CB1; C038362:pyrazolone; D000077285:Rimonabant