uu.seUppsala universitets publikasjoner
Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability
AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
AstraZeneca R&D, CVMD iMed DMPK, SE-43183 Molndal, Sweden..
AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
AstraZeneca R&D, RIA iMed, SE-43183 Molndal, Sweden..
Vise andre og tillknytning
2016 (engelsk)Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, nr 14, s. 6658-6670Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.

sted, utgiver, år, opplag, sider
2016. Vol. 59, nr 14, s. 6658-6670
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-303119DOI: 10.1021/acs.jmedchem.5b01871ISI: 000380730600006PubMedID: 27347787OAI: oai:DiVA.org:uu-303119DiVA, id: diva2:971250
Forskningsfinansiär
AstraZenecaTilgjengelig fra: 2016-09-15 Laget: 2016-09-15 Sist oppdatert: 2018-07-30bibliografisk kontrollert

Open Access i DiVA

Fulltekst mangler i DiVA

Andre lenker

Forlagets fulltekstPubMed

Søk i DiVA

Av forfatter/redaktør
Kihlberg, Jan
Av organisasjonen
I samme tidsskrift
Journal of Medicinal Chemistry

Søk utenfor DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 628 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf