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

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 (IC(50) = 12.3 μM). MDM2–p53 and MDMX–p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5-diphenyl-1H-pyrr...

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Detalles Bibliográficos
Autores principales: Blackburn, Tim J., Ahmed, Shafiq, Coxon, Christopher R., Liu, Junfeng, Lu, Xiaohong, Golding, Bernard T., Griffin, Roger J., Hutton, Claire, Newell, David R., Ojo, Stephen, Watson, Anna F., Zaytzev, Andrey, Zhao, Yan, Lunec, John, Hardcastle, Ian R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2013
Materias:
Chemistry
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777193/
https://www.ncbi.nlm.nih.gov/pubmed/24078862
http://dx.doi.org/10.1039/c3md00161j
Descripción
Sumario: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 (IC(50) = 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 IC(50) = 0.11 μM; MDMX IC(50) = 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 IC(50) = 0.15 μM; MDMX IC(50) = 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.

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