title: Synthesis and biological evaluation of benzodioxanylpiperazine derivatives as potent serotonin 5-HT(1A) antagonists: the discovery of Lecozotan.
abstract: A series of benzodioxanylpiperazine derivatives possessing a 4-aryl amide substituent was prepared and evaluated for 5-HT(1A) affinity and functional antagonist activity in vitro and in vivo. All of the compounds in this series possessed high affinity for the human 5-HT(1A) receptor and many displayed potent antagonist activity in vitro and varying degrees of intrinsic activity in vivo. Compound 11c (Lecozotan) was selected for further development and is currently in clinical trials.
authors.affiliation: Chemical and Screening Sciences and Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543-8000, USA. childew@wyeth.com
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Childers
authors.forename: Magid A
authors.initials: MA
authors.lastname: Abou-Gharbia
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kelly
authors.forename: Terrance H
authors.initials: TH
authors.lastname: Andree
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Harrison
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ho
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Hornby
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.forename: Lisa
authors.initials: L
authors.lastname: Potestio
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Rosenzweig-Lipson
authors.forename: Jean
authors.initials: J
authors.lastname: Schmid
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Smith
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Sukoff
authors.forename: Gan
authors.initials: G
authors.lastname: Zhang
authors.forename: Lee E
authors.initials: LE
authors.lastname: Schechter
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000096:biosynthesis; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004146:Dioxanes; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C500836:lecozotan; D000242:Cyclic AMP; D019204:GTP-Binding Proteins