schliessen

Filtern

 

Bibliotheken

Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.

Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. Whe... Full description

Journal Title: Journal of medicinal chemistry August 12, 2010, Vol.53(15), pp.5696-5706
Main Author: Xiong, Yifeng
Other Authors: Ullman, Brett , Choi, Jin-Sun Karoline , Cherrier, Martin , Strah-Pleynet, Sonja , Decaire, Marc , Dosa, Peter I , Feichtinger, Konrad , Teegarden, Bradley R , Frazer, John M , Yoon, Woo H , Shan, Yun , Whelan, Kevin , Hauser, Erin K , Grottick, Andrew J , Semple, Graeme , Al-Shamma, Hussien
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1520-4804 ; DOI: 10.1021/jm100479q
Link: http://search.proquest.com/docview/748950199/?pq-origsite=primo
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: proquest748950199
title: Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.
format: Article
creator:
  • Xiong, Yifeng
  • Ullman, Brett
  • Choi, Jin-Sun Karoline
  • Cherrier, Martin
  • Strah-Pleynet, Sonja
  • Decaire, Marc
  • Dosa, Peter I
  • Feichtinger, Konrad
  • Teegarden, Bradley R
  • Frazer, John M
  • Yoon, Woo H
  • Shan, Yun
  • Whelan, Kevin
  • Hauser, Erin K
  • Grottick, Andrew J
  • Semple, Graeme
  • Al-Shamma, Hussien
subjects:
  • Administration, Oral–Chemical Synthesis
  • Amides–Pharmacokinetics
  • Animals–Pharmacology
  • Biological Availability–Metabolism
  • Blood Proteins–Metabolism
  • Brain–Metabolism
  • Dogs–Chemical Synthesis
  • Drug Inverse Agonism–Pharmacokinetics
  • Haplorhini–Pharmacology
  • Humans–Chemical Synthesis
  • Male–Pharmacokinetics
  • Microsomes, Liver–Pharmacology
  • Piperazines–Drug Effects
  • Protein Binding–Drug Therapy
  • Pyrazoles–Drug Therapy
  • Rats–Drug Therapy
  • Rats, Sprague-Dawley–Drug Therapy
  • Serotonin 5-Ht2 Receptor Antagonists–Drug Therapy
  • Sleep–Drug Therapy
  • Sleep Initiation and Maintenance Disorders–Drug Therapy
  • Structure-Activity Relationship–Drug Therapy
  • 2-(4-(4-Bromo-1-Methyl-1h-Pyrazole-3-Carbonyl)Piperazin-1-Yl)-1-(4-Fluorophenyl)Ethanone
  • 2-(4-(4-Chloro-1-Methyl-1h-Pyrazole-3-Carbonyl)Piperazin-1-Yl)-1-(4-Fluorophenyl)Ethanone
  • Amides
  • Blood Proteins
  • Piperazines
  • Pyrazoles
  • Serotonin 5-Ht2 Receptor Antagonists
ispartof: Journal of medicinal chemistry, August 12, 2010, Vol.53(15), pp.5696-5706
description: Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.
language: eng
source:
identifier: E-ISSN: 1520-4804 ; DOI: 10.1021/jm100479q
fulltext: fulltext
issn:
  • 15204804
  • 1520-4804
url: Link


@attributes
ID314087493
RANK0.07
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
LOCALfalse
PrimoNMBib
record
control
sourcerecordid748950199
sourceidproquest
recordidTN_proquest748950199
sourcesystemPC
pqid748950199
display
typearticle
titleSynthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.
creatorXiong, Yifeng ; Ullman, Brett ; Choi, Jin-Sun Karoline ; Cherrier, Martin ; Strah-Pleynet, Sonja ; Decaire, Marc ; Dosa, Peter I ; Feichtinger, Konrad ; Teegarden, Bradley R ; Frazer, John M ; Yoon, Woo H ; Shan, Yun ; Whelan, Kevin ; Hauser, Erin K ; Grottick, Andrew J ; Semple, Graeme ; Al-Shamma, Hussien
contributorXiong, Yifeng (correspondence author) ; Xiong, Yifeng (record owner)
ispartofJournal of medicinal chemistry, August 12, 2010, Vol.53(15), pp.5696-5706
identifierE-ISSN: 1520-4804 ; DOI: 10.1021/jm100479q
subjectAdministration, Oral–Chemical Synthesis ; Amides–Pharmacokinetics ; Animals–Pharmacology ; Biological Availability–Metabolism ; Blood Proteins–Metabolism ; Brain–Metabolism ; Dogs–Chemical Synthesis ; Drug Inverse Agonism–Pharmacokinetics ; Haplorhini–Pharmacology ; Humans–Chemical Synthesis ; Male–Pharmacokinetics ; Microsomes, Liver–Pharmacology ; Piperazines–Drug Effects ; Protein Binding–Drug Therapy ; Pyrazoles–Drug Therapy ; Rats–Drug Therapy ; Rats, Sprague-Dawley–Drug Therapy ; Serotonin 5-Ht2 Receptor Antagonists–Drug Therapy ; Sleep–Drug Therapy ; Sleep Initiation and Maintenance Disorders–Drug Therapy ; Structure-Activity Relationship–Drug Therapy ; 2-(4-(4-Bromo-1-Methyl-1h-Pyrazole-3-Carbonyl)Piperazin-1-Yl)-1-(4-Fluorophenyl)Ethanone ; 2-(4-(4-Chloro-1-Methyl-1h-Pyrazole-3-Carbonyl)Piperazin-1-Yl)-1-(4-Fluorophenyl)Ethanone ; Amides ; Blood Proteins ; Piperazines ; Pyrazoles ; Serotonin 5-Ht2 Receptor Antagonists
languageeng
source
descriptionRecent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.
version3
lds50peer_reviewed
links
openurl$$Topenurl_article
openurlfulltext$$Topenurlfull_article
backlink$$Uhttp://search.proquest.com/docview/748950199/?pq-origsite=primo$$EView_record_in_ProQuest_(subscribers_only)
search
creatorcontrib
0Xiong, Yifeng
1Ullman, Brett
2Choi, Jin-Sun Karoline
3Cherrier, Martin
4Strah-Pleynet, Sonja
5Decaire, Marc
6Dosa, Peter I
7Feichtinger, Konrad
8Teegarden, Bradley R
9Frazer, John M
10Yoon, Woo H
11Shan, Yun
12Whelan, Kevin
13Hauser, Erin K
14Grottick, Andrew J
15Semple, Graeme
16Al-Shamma, Hussien
titleSynthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.
subject
0Administration, Oral–Chemical Synthesis
1Amides–Pharmacokinetics
2Animals–Pharmacology
3Biological Availability–Metabolism
4Blood Proteins–Metabolism
5Brain–Metabolism
6Dogs–Chemical Synthesis
7Drug Inverse Agonism–Pharmacokinetics
8Haplorhini–Pharmacology
9Humans–Chemical Synthesis
10Male–Pharmacokinetics...
general
0English
110.1021/jm100479q
2MEDLINE (ProQuest)
3ProQuest Biological Science Collection
4ProQuest Natural Science Collection
5ProQuest SciTech Collection
6Biological Science Database
7Natural Science Collection
8SciTech Premium Collection
9Health Research Premium Collection
10Health Research Premium Collection (Alumni edition)
11Biological Science Index (ProQuest)
sourceidproquest
recordidproquest748950199
issn
015204804
11520-4804
rsrctypearticle
creationdate2010
addtitleJournal of medicinal chemistry
searchscope
01007527
11007944
21009130
310000004
410000038
510000050
610000120
710000159
810000238
910000253
1010000260
1110000270
1210000271
1310000302
1410000350
15proquest
scope
01007527
11007944
21009130
310000004
410000038
510000050
610000120
710000159
810000238
910000253
1010000260
1110000270
1210000271
1310000302
1410000350
15proquest
lsr43
01007527false
11007944false
21009130false
310000004false
410000038false
510000050false
610000120false
710000159false
810000238false
910000253false
1010000260false
1110000270false
1210000271false
1310000302false
1410000350false
contributorXiong, Yifeng
startdate20100812
enddate20100812
citationpf 5696 pt 5706 vol 53 issue 15
lsr30VSR-Enriched:[pqid, issn, description]
sort
titleSynthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.
authorXiong, Yifeng ; Ullman, Brett ; Choi, Jin-Sun Karoline ; Cherrier, Martin ; Strah-Pleynet, Sonja ; Decaire, Marc ; Dosa, Peter I ; Feichtinger, Konrad ; Teegarden, Bradley R ; Frazer, John M ; Yoon, Woo H ; Shan, Yun ; Whelan, Kevin ; Hauser, Erin K ; Grottick, Andrew J ; Semple, Graeme ; Al-Shamma,...
creationdate20100812
lso0120100812
facets
frbrgroupid7188448502998894290
frbrtype5
newrecords20181218
languageeng
creationdate2010
topic
0Administration, Oral–Chemical Synthesis
1Amides–Pharmacokinetics
2Animals–Pharmacology
3Biological Availability–Metabolism
4Blood Proteins–Metabolism
5Brain–Metabolism
6Dogs–Chemical Synthesis
7Drug Inverse Agonism–Pharmacokinetics
8Haplorhini–Pharmacology
9Humans–Chemical Synthesis
10Male–Pharmacokinetics...
collection
0MEDLINE (ProQuest)
1ProQuest Biological Science Collection
2ProQuest Natural Science Collection
3ProQuest SciTech Collection
4Biological Science Database
5Natural Science Collection
6SciTech Premium Collection
7Health Research Premium Collection
8Health Research Premium Collection (Alumni edition)
9Biological Science Index (ProQuest)
prefilterarticles
rsrctypearticles
creatorcontrib
0Xiong, Yifeng
1Ullman, Brett
2Choi, Jin-Sun Karoline
3Cherrier, Martin
4Strah-Pleynet, Sonja
5Decaire, Marc
6Dosa, Peter I
7Feichtinger, Konrad
8Teegarden, Bradley R
9Frazer, John M
10Yoon, Woo H
11Shan, Yun
12Whelan, Kevin
13Hauser, Erin K
14Grottick, Andrew J
15Semple, Graeme
16Al-Shamma, Hussien
jtitleJournal of medicinal chemistry
toplevelpeer_reviewed
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
aulast
0Xiong
1Ullman
2Choi
3Cherrier
4Strah-Pleynet
5Decaire
6Dosa
7Feichtinger
8Teegarden
9Frazer
10Yoon
11Shan
12Whelan
13Hauser
14Grottick
15Semple
16Al-Shamma
aufirst
0Yifeng
1Brett
2Jin-Sun Karoline
3Martin
4Sonja
5Marc
6Peter I
7Konrad
8Bradley R
9John M
10Woo H
11Yun
12Kevin
13Erin K
14Andrew J
15Graeme
16Hussien
au
0Xiong, Yifeng
1Ullman, Brett
2Choi, Jin-Sun Karoline
3Cherrier, Martin
4Strah-Pleynet, Sonja
5Decaire, Marc
6Dosa, Peter I
7Feichtinger, Konrad
8Teegarden, Bradley R
9Frazer, John M
10Yoon, Woo H
11Shan, Yun
12Whelan, Kevin
13Hauser, Erin K
14Grottick, Andrew J
15Semple, Graeme
16Al-Shamma, Hussien
addauXiong, Yifeng
atitleSynthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.
jtitleJournal of medicinal chemistry
risdate20100812
volume53
issue15
spage5696
epage5706
pages5696-5706
eissn1520-4804
formatjournal
genrearticle
ristypeJOUR
doi10.1021/jm100479q
urlhttp://search.proquest.com/docview/748950199/
issn00222623
date2010-08-12