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

Tim J. Blackburn, Shafiq Ahmed, Christopher R. Coxon, Junfeng Liu, Xiaohong Lu, Bernard T. Golding, Roger J. Griffin, Claire Hutton, David R. Newell, Stephen Ojo, Anna F. Watson, Andrey Zaytzev, Yan Zhao, John Lunec, Ian R. Hardcastle

Research output: Contribution to journalArticle

18 Citations (Scopus)
1 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1297-1304
Number of pages8
JournalMedChemComm
Volume4
Issue number9
DOIs
Publication statusPublished - 1 Sep 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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