Discovery of 5‑Cyano-6-phenylpyrimidin Derivatives Containing an Acylurea Moiety as Orally Bioavailable Reversal Agents against P‑Glycoprotein-Mediated Mutidrug Resistance

P-glycoprotein (ABCB1)-mediated multidrug
resistance (MDR) has
become a major obstacle in successful cancer chemotherapy, which attracted
much effort to develop clinically useful compounds to reverse MDR.
Here, we designed and synthesized a novel series of derivatives with
a 5-cyano-6-phenylpyrimidine scaffold and evaluated their potential
reversal activities against MDR. Among these compounds, 55, containing an acylurea appendage, showed the most potent activity
in reversing paclitaxel resistance in SW620/AD300 cells. Further studies
demonstrated 55 could increase accumulation of PTX, interrupt
ABCB1-mediated Rh123 accumulation and efflux, stimulate ABCB1 ATPase
activity, and especially have no effect on CYP3A4 activity, which
avoid drug interaction caused toxicity. More importantly, 55 significantly enhanced the efficacy of PTX against the SW620/AD300
cell xenograft without obvious side effects for orally intake. Given
all that, the pyrimidine-acylurea based ABCB1 inhibitor may be a promising
lead in developing new efficacious ABCB1-dependent MDR modulator.