title: Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT(2C) receptor agonists.
abstract: The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. guohua.zhao@bms.com
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Chet
authors.initials: C
authors.lastname: Kwon
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Bisaha
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stein
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Xueying
authors.initials: X
authors.lastname: Cao
authors.forename: Thao
authors.initials: T
authors.lastname: Ung
authors.forename: Ginger
authors.initials: G
authors.lastname: Wu
authors.forename: Chen-Pin
authors.initials: CP
authors.lastname: Hung
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Malmstrom
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Qinling
authors.initials: Q
authors.lastname: Qu
authors.forename: Jinping
authors.initials: J
authors.lastname: Gan
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: 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: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D011719:Pyrazines; D044405:Receptor, Serotonin, 5-HT2C