Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors

A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are describ...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-03, Vol.22 (6), p.2230-2234
Hauptverfasser:	Lin, Hong, Erhard, Karl, Hardwicke, Mary Ann, Luengo, Juan I., Mack, James F., McSurdy-Freed, Jeanelle, Plant, Ramona, Raha, Kaushik, Rominger, Cynthia M., Sanchez, Robert M., Schaber, Michael D., Schulz, Mark J., Spengler, Michael D., Tedesco, Rosanna, Xie, Ren, Zeng, Jin J., Rivero, Ralph A.
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Binding Sites Biological and medical sciences Breast Neoplasms Cell Line, Tumor chemotypes Drug Screening Assays, Antitumor enantiomers Female Gene Deletion Homology model Humans Imidazoles - chemical synthesis Imidazoles - pharmacology Isoenzymes - antagonists & inhibitors Isoenzymes - metabolism Kinetics Medical sciences Models, Molecular Pharmacology. Drug treatments Phosphatidylinositol 3-kinase Phosphatidylinositol 3-Kinase - antagonists & inhibitors Phosphatidylinositol 3-Kinase - metabolism PI3K-beta inhibitor Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology PTEN Phosphohydrolase - deficiency PTEN Phosphohydrolase - genetics PTEN-null Pyrimidinones - chemical synthesis Pyrimidinones - pharmacology Structure-Activity Relationship structure-activity relationships
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Zusammenfassung:	A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.01.092