Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2–p53 and MDMX–p53 protein–protein interactions

Abstract

Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2<i>H</i>)-ylidene)methyl)-2,5-dimethyl-1<i>H</i>-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[<i>b</i>]thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC₅₀ = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5-diphenyl-1<i>H</i>-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1<i>H</i>,5<i>H</i>)-dione (MDM2 IC₅₀ = 0.11 μM; MDMX IC₅₀ = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1<i>H</i>-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1<i>H</i>,3<i>H</i>,5<i>H</i>)-trione (MDM2 IC₅₀ = 0.15 μM; MDMX IC₅₀ = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX-p53 activity but not for MDM2-p53 inhibition.