Synthesis and biological evaluation of benzodioxanylpiperazine derivatives as potent serotonin 5-HT(1A) antagonists: the discovery of Lecozotan.
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.
Childers
Wayne E
WE
Chemical and Screening Sciences and Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543-8000, USA. childew@wyeth.com
Abou-Gharbia
Magid A
MA
Kelly
Michael G
MG
Andree
Terrance H
TH
Harrison
Boyd L
BL
Ho
Douglas M
DM
Hornby
Geoffrey
G
Huryn
Donna M
DM
Potestio
Lisa
L
Rosenzweig-Lipson
Sharon J
SJ
Schmid
Jean
J
Smith
Deborah L
DL
Sukoff
Stacey J
SJ
Zhang
Gan
G
Schechter
Lee E
LE
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
D004146:Dioxanes; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C500836:lecozotan; D000242:Cyclic AMP; D019204:GTP-Binding Proteins