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

Blackburn, TJ, Ahmed, Shafiq, Coxon, CR, Liu, J, Lu, X, Golding, BT, Griffin, RJ, Hutton, C, Newell, DR, Ojo, S, Watson, AF, Zaytzev, A, Zhao, Y, Lunec, J and Hardcastle, IR (2013) Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions. Med. Chem. Commun., 4 (9). pp. 1297-1304.

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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.

Item Type: Article
Subjects: Sciences
Divisions: Faculty of Applied Sciences
Faculty of Applied Sciences > Department of Pharmacy Health and Wellbeing
Health Sciences and Wellbeing Beacon
Depositing User: Paula Normington
Date Deposited: 16 Feb 2016 12:12
Last Modified: 16 Feb 2016 12:12
URI: http://sure.sunderland.ac.uk/id/eprint/6008

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