Dual inhibitors of the human blood-brain barrier drug efflux transporters P-glycoprotein and ABCG2 based on the antiviral azidothymidine

作者：Namanja Magliano Hilda A; Bohn Kelsey; Agrawal Neha; Willoughby Meghan E; Hrycyna Christine A; Chmielewski Jean^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(19): 5128-5132.

DOI：10.1016/j.bmc.2017.07.001

• Blood-brain barrier
• P-glycoprotein
• ABCG2
• AZT
• Inhibition

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 [I-125]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.

• 出版日期2017-10-1