Constrained analogs of CB-1 antagonists: 1,5,6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives.
A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.
Smith
Roger A
RA
Department of Chemistry Research, Bayer HealthCare, Pharmaceuticals Division, West Haven, CT 06516, USA. roger.smith.b@bayer.com
Fathi
Zahra
Z
Brown
Su-Ellen
SE
Choi
Soongyu
S
Fan
Jianmei
J
Jenkins
Susan
S
Kluender
Harold C E
HC
Konkar
Anish
A
Lavoie
Rico
R
Mays
Ronald
R
Natoli
Jennifer
J
O'Connor
Stephen J
SJ
Ortiz
Astrid A
AA
Podlogar
Brent
B
Taing
Christy
C
Tomlinson
Susan
S
Tritto
Theresa
T
Zhang
Zhonghua
Z
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004435:Eating / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D009765:Obesity / Q000188:drug therapy; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013329:Structure-Activity Relationship; D015430:Weight Gain / Q000187:drug effects
C518526:1,5,6,7-Tetrahydro-4H-pyrrolo(3,2-c)pyridine-4-one; D019440:Anti-Obesity Agents; D010880:Piperidines; D011720:Pyrazoles; D011728:Pyridones; D011758:Pyrroles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant