umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors
Visa övriga samt affilieringar
2013 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, nr 21, s. 8484-8496Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, Si), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 mu M), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 mu M). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 mu M and 16% inhibition at 10 mu M, respectively). The FAAH selectivity of the compound Si over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected Senantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2013. Vol. 56, nr 21, s. 8484-8496
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
URN: urn:nbn:se:umu:diva-84115DOI: 10.1021/jm400923sISI: 000327111100021OAI: oai:DiVA.org:umu-84115DiVA, id: diva2:680415
Tillgänglig från: 2013-12-18 Skapad: 2013-12-16 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltext

Personposter BETA

Cipriano, MariateresaFowler, Christopher J.

Sök vidare i DiVA

Av författaren/redaktören
Cipriano, MariateresaFowler, Christopher J.
Av organisationen
Farmakologi
I samma tidskrift
Journal of Medicinal Chemistry
Farmakologi och toxikologi

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 165 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf