title: Isoindolone derivatives, a new class of 5-HT2C antagonists: synthesis and biological evaluation.
abstract: Two independent approaches resulted in the identification of a series of isoindolone derivatives as potent and selective 5-HT2C antagonists. From a Medicinal Chemistry perspective this template was considered interesting as it allowed the incorporation of the carbon-carbon double bond of an earlier dihydropyrrolone series in an aromatic system within a comparatively simple and compact motif. Additionally an in silico screening approach of the corporate database using a 5-HT2C pharmacophore model resulted in the identification of a related structure containing this template. The strategy used to optimise potency at the target receptor and to improve the pharmacokinetic profile is described, resulting in molecules combining high potency with good selectivity and oral bioavailability.
authors.affiliation: GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy. dieter.w.hamprecht@gsk.com
authors.forename: Dieter
authors.initials: D
authors.lastname: Hamprecht
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Micheli
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tedesco
authors.forename: Anna
authors.initials: A
authors.lastname: Checchia
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Marcella
authors.initials: M
authors.lastname: Petrone
authors.forename: Silvia
authors.initials: S
authors.lastname: Terreni
authors.forename: Martyn
authors.initials: M
authors.lastname: Wood
mesh_terms: D000818:Animals; D001682:Biological Availability; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D054833:Isoindoles; D008297:Male; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D007211:Indoles; C110621:Isoindol-1-one; D054833:Isoindoles; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists