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 (+3 others)
2013 MedChemComm  
Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)methyl)-2,5-dimethyl-1Hpyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC 50 ¼ 12.3 mM). 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 IC 50 ¼ 0.11 mM; MDMX IC 50 ¼ 4.2 mM) and
more » ... (MDM2 IC 50 ¼ 0.15 mM; MDMX IC 50 ¼ 4.2 mM), 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.
doi:10.1039/c3md00161j pmid:24078862 pmcid:PMC3777193 fatcat:yg43jtpwp5hgtmb4guay4iij2u