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

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