Back to Search
Start Over
Dual inhibitors of the human blood-brain barrier drug efflux transporters P-glycoprotein and ABCG2 based on the antiviral azidothymidine.
- Source :
-
Bioorganic & Medicinal Chemistry . Oct2017, Vol. 25 Issue 19, p5128-5132. 5p. - Publication Year :
- 2017
-
Abstract
- The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone. The homodimers function by interacting with the transporter drug binding sites as demonstrated by competition studies with the photo-affinity agent and P-gp/ABCG2 substrate [ 125 I]iodoarylazidoprazosin. As such, these dual inhibitors of both efflux transporters provide a model for the future development of delivery vehicles for antiretroviral agents to the brain. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 25
- Issue :
- 19
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 125312561
- Full Text :
- https://doi.org/10.1016/j.bmc.2017.07.001