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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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-03, Vol.22 (6), p.2230-2234
Main Authors: 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: Article
Language:English
Subjects:
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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Summary: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