Functional induction of P-glycoprotein efflux pump by phenyl benzenesulfonamides: Synthesis and biological evaluation of T0901317 analogs

• P-gp induction activity of a PXR activator T0901317 has been reported.
• Structure-activity relationship of T0901317 has been established.
• Analogs (e.g. 26e) displaying promising P-gp induction have been identified.
• The potent P-gp induction activity was also observed at 0.3 μM.
• These compounds displayed excellent therapeutic window.

N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317, 6) is a potent activator of pregnane-X-receptor (PXR), which is a nuclear receptor controlling P-gp expression. Herein, we aimed to investigate P-gp induction activity of T0901317 and establish its structure-activity relationship. T0901317 along with a series of N-triazolyl-methylene-linked benzenesulfonamides were synthesized and screened for P-gp induction activity using a rhodamine-123 based efflux assay in the P-gp overexpressing human adenocarcinoma LS-180 cells, wherein several compounds showed potent P-gp induction activity at 5 μM. Treatment with benzene sulphonamides led to the decrease in intracellular accumulation of a fluorescent P-gp substrate rhodamine-123 up to 48% (control 100%). In the western-blot studies, T0901317 (6) and its triazole linked analog 26e at 5 μM displayed induction of P-gp expression in LS180 cells. These compounds were non-toxic in LS-180 and human neuroblastoma SH-SY5Y cells (IC50 > 50 μM). The compound 26e showed significant P-gp induction even at 0.3 μM, indicating an excellent therapeutic window. These results clearly indicate promise of this class of compounds as potential agents to enhance amyloid-β clearance in Alzheimers patients.

We report P-gp induction activity of a PXR activator T0901317 and its structure-activity relationship. Analogs displaying promising P-gp induction have been identified.Figure optionsDownload as PowerPoint slide