Synthesis and structure-activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potent β isoform selective phosphatidylinositol 3-kinase inhibitors

Robert M Sanchez; Karl Erhard; Mary Ann Hardwicke; Hong Lin; Jeanelle McSurdy-Freed; Ramona Plant; Kaushik Raha; Cynthia M Rominger; Michael D Schaber; Michael D Spengler; Michael L Moore; Hongyi Yu; Juan I Luengo; Rosanna Tedesco; Ralph A Rivero

doi:10.1016/j.bmcl.2012.03.039

Synthesis and structure-activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potent β isoform selective phosphatidylinositol 3-kinase inhibitors

Bioorg Med Chem Lett. 2012 May 1;22(9):3198-202. doi: 10.1016/j.bmcl.2012.03.039. Epub 2012 Mar 16.

Authors

Robert M Sanchez¹, Karl Erhard, Mary Ann Hardwicke, Hong Lin, Jeanelle McSurdy-Freed, Ramona Plant, Kaushik Raha, Cynthia M Rominger, Michael D Schaber, Michael D Spengler, Michael L Moore, Hongyi Yu, Juan I Luengo, Rosanna Tedesco, Ralph A Rivero

Affiliation

¹ Cancer Metabolism Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. [email protected]

PMID: 22475557
DOI: 10.1016/j.bmcl.2012.03.039

Abstract

A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (∼ 0.100 μM IC(50)) growth inhibition in a PTEN deficient cancer cell line.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
PTEN Phosphohydrolase / deficiency
Phosphoinositide-3 Kinase Inhibitors*
Protein Isoforms / antagonists & inhibitors
Protein Kinase Inhibitors / chemistry*
Pyrimidines
Structure-Activity Relationship
Substrate Specificity

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Isoforms
Protein Kinase Inhibitors
Pyrimidines
PTEN Phosphohydrolase