Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

Bioorg Med Chem Lett. 2012 Oct 15;22(20):6381-4. doi: 10.1016/j.bmcl.2012.08.072. Epub 2012 Aug 25.

Abstract

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.

MeSH terms

  • Anilides / chemistry
  • Anilides / pharmacokinetics
  • Anilides / pharmacology
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Crystallography, X-Ray
  • Female
  • Gene Deletion
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Models, Molecular
  • PTEN Phosphohydrolase / genetics
  • Phosphoinositide-3 Kinase Inhibitors*
  • Prostate / cytology
  • Prostate / drug effects
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / genetics
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacokinetics
  • Pyrimidinones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anilides
  • Antineoplastic Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • Pyrimidinones
  • Class Ia Phosphatidylinositol 3-Kinase
  • PTEN Phosphohydrolase
  • PTEN protein, human