title: Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders.
abstract: We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT(2A) and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT(2A) antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.
authors.affiliation: Intra-Cellular Therapies, Inc. , 3960 Broadway, New York, New York 10032, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
authors.forename: Taekyu
authors.initials: T
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Tomesch
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: J David
authors.initials: JD
authors.lastname: Beard
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Snyder
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhu
authors.forename: Youyi
authors.initials: Y
authors.lastname: Peng
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hendrick
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Vanover
authors.forename: Robert E
authors.initials: RE
authors.lastname: Davis
authors.forename: Sharon
authors.initials: S
authors.lastname: Mates
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Wennogle
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D055808:Drug Discovery; D004597:Electroshock; D007202:Indicators and Reagents; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy*; D009422:Nervous System Diseases / Q000188:drug therapy*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011814:Quipazine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D018759:Adrenergic Uptake Inhibitors; D007202:Indicators and Reagents; D011810:Quinoxalines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D011814:Quipazine