Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists

Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical propert...

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Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 20; no. 23; pp. 7137 - 7141
Main Authors HAWRYLUK, Natalie A, MERIT, Jeffrey E, FREEDMAN, Jamie M, SCOTT, Brian P, WICKENDEN, Alan D, CHAPLAN, Sandra R, BREITENBUCHER, J. Guy, LEBSACK, Alec D, BRANSTETTER, Bryan J, HACK, Michael D, SWANSON, Nadia, HONG AO, MAHER, Michael P, BHATTACHARYA, Anindya, QI WANG
Format Journal Article
LanguageEnglish
Published Amsterdam Elsevier 01.12.2010
Subjects
Analgesics
Animals
Antagonists
Azepines - chemical synthesis
Azepines - pharmacology
Biological and medical sciences
Drug Discovery
Medical sciences
Neuropharmacology
Pharmacology. Drug treatments
Rats
Structure-Activity Relationship
TRPV Cation Channels - antagonists & inhibitors
Rat
Rodentia
Vanilloid
TRPV1
In vitro
Tetrahydro-pyrimdoazepine
In vivo
Vertebrata
VR1 vanilloid receptor
TRPV1 vanilloid receptor
Mammalia
Analgesic
TRP ion channel
Structure activity relation
Animal
Antagonist
Fluorine Organic compounds
Pharmacokinetics
Chemical synthesis
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Summary:Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties.
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ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.09.023