The clearance of amyloid-beta is mediated by P-glycoprotein (P-gp) transporter pump located at the blood brain barrier. Therefore, the induction of P-gp has been considered as a potential therapeutic strategy for treatment of Alzheimer's disease. The expression of P-gp is regulated through a nuclear receptor - pregnane-X-receptor (PXR). Thus, herein we investigated the potential of a known pregnane-X-receptor (PXR) activator diphosphonate ester SR12813 (6a) for P-gp induction activity and further studied its structure-activity relationship. A diphosphonate ester SR12813 along with a three series of analogs viz. aryl alkylidene, aryl alkynyl, and aryl α-amino phosphonate esters were synthesized and screened for P-gp induction activity in P-gp overexpressing adenocarcinoma LS180 cells using rhodamine-123 efflux assay. The parent compound SR12813 along with several new analogs displayed P-gp induction activity at 5 µM. The western-blot analysis indicated that tetraethyl-2 phenylethene-1,1-diyldiphosphonate (6c) and tetraethyl-2-(anthracene-10-yl)ethene-1,1-diyldiphosphonate (6s) showed 7-8 fold increase in P-gp expression in LS180 cells. The diphosphonate ester 6c displayed excellent aqueous solubility, no cytochrome P450 inhibition liability and no efflux pump substrate liability. Furthermore, it possesses excellent oral pharmacokinetic profile in BALB/c mice with AUC0-∞ of 2067 ng·h/mL and 37.6% oral bioavailability. The results presented here clearly indicate the potential of this scaffold to increase the clearance of brain Aβ across the BBB and thus its promise for development as potential anti-Alzheimer agents.