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Issue 9, 2013
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Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2–p53 and MDMX–p53 proteinprotein interactions

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Abstract

Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b]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-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC50 = 0.11 μM; MDMX IC50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-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.

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

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Publication details

The article was received on 11 Jun 2013, accepted on 16 Jul 2013 and first published on 18 Jul 2013


Article type: Concise Article
DOI: 10.1039/C3MD00161J
Citation: Med. Chem. Commun., 2013,4, 1297-1304
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    Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2–p53 and MDMX–p53 proteinprotein interactions

    T. J. Blackburn, S. Ahmed, C. R. Coxon, J. Liu, X. Lu, B. T. Golding, R. J. Griffin, C. Hutton, D. R. Newell, S. Ojo, A. F. Watson, A. Zaytzev, Y. Zhao, J. Lunec and I. R. Hardcastle, Med. Chem. Commun., 2013, 4, 1297
    DOI: 10.1039/C3MD00161J

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