title: Constrained analogs of CB-1 antagonists: 1,5,6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives.
abstract: 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.
authors.affiliation: Department of Chemistry Research, Bayer HealthCare, Pharmaceuticals Division, West Haven, CT 06516, USA. roger.smith.b@bayer.com
authors.forename: Roger A
authors.initials: RA
authors.lastname: Smith
authors.forename: Zahra
authors.initials: Z
authors.lastname: Fathi
authors.forename: Su-Ellen
authors.initials: SE
authors.lastname: Brown
authors.forename: Soongyu
authors.initials: S
authors.lastname: Choi
authors.forename: Jianmei
authors.initials: J
authors.lastname: Fan
authors.forename: Susan
authors.initials: S
authors.lastname: Jenkins
authors.forename: Harold C E
authors.initials: HC
authors.lastname: Kluender
authors.forename: Anish
authors.initials: A
authors.lastname: Konkar
authors.forename: Rico
authors.initials: R
authors.lastname: Lavoie
authors.forename: Ronald
authors.initials: R
authors.lastname: Mays
authors.forename: Jennifer
authors.initials: J
authors.lastname: Natoli
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Connor
authors.forename: Astrid A
authors.initials: AA
authors.lastname: Ortiz
authors.forename: Brent
authors.initials: B
authors.lastname: Podlogar
authors.forename: Christy
authors.initials: C
authors.lastname: Taing
authors.forename: Susan
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Theresa
authors.initials: T
authors.lastname: Tritto
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhang
mesh_terms: 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
chemical_list: 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