Structure-Based Design, Synthesis, and Biological Evaluation of New Triazolo[1,5-]Pyrimidine Derivatives as Highly Potent and Orally Active ABCB1 Modulators.

ABCB1 is a promising therapeutic target for overcoming multidrug resistance (MDR). In this work, we reported the structure-based design of triazolo[1,5-]pyrimidines as new ABCB1 modulators, of which significantly increased sensitization of ABCB1-overexpressed SW620/Ad300 cells to paclitaxel (PTX) (IC = 22.02 nM). Mechanistic studies indicated that significantly increased the intracellular concentration of PTX and [H]-PTX while decreasing the efflux of [H]-PTX in SW620/Ad300 cells by inhibiting the efflux function of ABCB1. The cellular thermal shift assay suggested that could stabilize ABCB1 by directly binding to ABCB1. could stimulate the activity of ABCB1 ATPase but had almost no inhibitory activity against CYP3A4. Importantly, increased the sensitivity of SW620/Ad300 cells to PTX without observed toxicity. Collectively, is a highly potent and orally active ABCB1 modulator capable of overcoming MDR. The triazolo[1,5-]pyrimidine may be a promising scaffold for developing more potent ABCB1 modulators.