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Issue 9, 2013
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Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2–p53 and MDMX–p53 protein–protein 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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Supplementary files

Article information


Submitted
11 Jun 2013
Accepted
16 Jul 2013
First published
18 Jul 2013

This article is Open Access

Med. Chem. Commun., 2013,4, 1297-1304
Article type
Concise Article

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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