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

Abstract

ABCB1 is a promising therapeutic target for overcoming multidrug resistance (MDR). In this work, we reported the structure-based design of triazolo[1,5-<i>a</i>]pyrimidines as new ABCB1 modulators, of which <b>WS-691</b> significantly increased sensitization of ABCB1-overexpressed SW620/Ad300 cells to paclitaxel (PTX) (IC₅₀ = 22.02 nM). Mechanistic studies indicated that <b>WS-691</b> significantly increased the intracellular concentration of PTX and [³H]-PTX while decreasing the efflux of [³H]-PTX in SW620/Ad300 cells by inhibiting the efflux function of ABCB1. The cellular thermal shift assay suggested that <b>WS-691</b> could stabilize ABCB1 by directly binding to ABCB1. <b>WS-691</b> could stimulate the activity of ABCB1 ATPase but had almost no inhibitory activity against CYP3A4. Importantly, <b>WS-691</b> increased the sensitivity of SW620/Ad300 cells to PTX <i>in vivo</i> without observed toxicity. Collectively, <b>WS-691</b> is a highly potent and orally active ABCB1 modulator capable of overcoming MDR. The triazolo[1,5-<i>a</i>]pyrimidine may be a promising scaffold for developing more potent ABCB1 modulators.