title: Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
abstract: Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. dean.wacker@bms.com
authors.forename: Dean A
authors.initials: DA
authors.lastname: Wacker
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Varnes
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Malmstrom
authors.forename: Xueying
authors.initials: X
authors.lastname: Cao
authors.forename: Chen-Pin
authors.initials: CP
authors.lastname: Hung
authors.forename: Thao
authors.initials: T
authors.lastname: Ung
authors.forename: Ginger
authors.initials: G
authors.lastname: Wu
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Eva
authors.initials: E
authors.lastname: Zuvich
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thomas
authors.forename: William J
authors.initials: WJ
authors.lastname: Keim
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Cullen
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Rohrbach
authors.forename: Qinling
authors.initials: Q
authors.lastname: Qu
authors.forename: Rangaraj
authors.initials: R
authors.lastname: Narayanan
authors.forename: Karen
authors.initials: K
authors.lastname: Rossi
authors.forename: Evan
authors.initials: E
authors.lastname: Janovitz
authors.forename: Lois
authors.initials: L
authors.lastname: Lehman-McKeeman
authors.forename: Mary F
authors.initials: MF
authors.lastname: Malley
authors.forename: James
authors.initials: J
authors.lastname: Devenny
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Pelleymounter
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Miller
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D003216:Conditioning, Operant; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054833:Isoindoles; D008297:Male; D051379:Mice; D009336:Necrosis; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000473:pathology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D058826:Serotonin 5-HT2 Receptor Agonists; D013237:Stereoisomerism; D015430:Weight Gain / Q000187:drug effects
chemical_list: C519109:9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino(2,1-a)isoindol-6(2H)-one; D019440:Anti-Obesity Agents; D007211:Indoles; D054833:Isoindoles; D011719:Pyrazines; D058826:Serotonin 5-HT2 Receptor Agonists