Improvement of the synthesis and pharmacokinetic properties of chromenotriazolopyrimidine MDM2-p53 protein-protein inhibitors

Human murine double minute 2 (MDM2) is a negative regulator of p53, which plays an important role in cell cycle and apoptosis. We report several optimizations to the synthesis of the chromenotriazolopyrimidine series of MDM2-p53 protein-protein interaction inhibitors. Additionally, the in vitro and...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (9), p.2752-2755
Hauptverfasser:	Beck, Hilary P., DeGraffenreid, Michael, Fox, Brian, Allen, John G., Rew, Yosup, Schneider, Stephen, Saiki, Anne Y., Yu, Dongyin, Oliner, Jonathan D., Salyers, Kevin, Ye, Qiuping, Olson, Steven
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antineoplastic agents apoptosis Biological and medical sciences cell cycle Drug Stability General aspects Humans Infusion Pumps Inhibitory Concentration 50 Medical sciences mice Molecular Structure Oncology Pharmacokinetics Pharmacology. Drug treatments protein-protein interactions Protein–protein interaction Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors Pyrimidines - chemical synthesis Pyrimidines - pharmacokinetics Rats Solubility Structure-Activity Relationship Tumor Suppressor Protein p53 - antagonists & inhibitors
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Zusammenfassung:	Human murine double minute 2 (MDM2) is a negative regulator of p53, which plays an important role in cell cycle and apoptosis. We report several optimizations to the synthesis of the chromenotriazolopyrimidine series of MDM2-p53 protein-protein interaction inhibitors. Additionally, the in vitro and in vivo stability, pharmacokinetic properties and solubility were improved through N-substitution.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.11.027