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Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2 H )-ylidene)methyl)-2,5-dimethyl-1 H -pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC 50 = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5-diphenyl-1 H -pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1 H ,5 H )-dione (MDM2 IC 50 = 0.11 μM; MDMX IC 50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1 H -pyrrol-3-yl)methylene)pyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (MDM2 IC 50 = 0.15 μM; MDMX IC 50 = 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.

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