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