title: Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.
abstract: Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
authors.affiliation: Research & Development, Bristol-Myers Squibb Co, PO Box 4000, Princeton, NJ 08543, United States. saleem.ahmad@bms.com
authors.forename: Saleem
authors.initials: S
authors.lastname: Ahmad
authors.forename: Khehyong
authors.initials: K
authors.lastname: Ngu
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Miller
authors.forename: Ginger
authors.initials: G
authors.lastname: Wu
authors.forename: Chen-pin
authors.initials: CP
authors.lastname: Hung
authors.forename: Sarah
authors.initials: S
authors.lastname: Malmstrom
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Eva
authors.initials: E
authors.lastname: O'Tanyi
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: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Thao
authors.initials: T
authors.lastname: Ung
authors.forename: Qinling
authors.initials: Q
authors.lastname: Qu
authors.forename: Jinping
authors.initials: J
authors.lastname: Gan
authors.forename: Rangaraj
authors.initials: R
authors.lastname: Narayanan
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Pelleymounter
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D004435:Eating / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D052999:Quinazolinones / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D052999:Quinazolinones; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists