Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1212-6. doi: 10.1016/j.bmcl.2013.01.019. Epub 2013 Jan 18.

Abstract

The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).

MeSH terms

  • Benzamides
  • Cell Growth Processes / drug effects
  • Cells, Cultured
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Morpholines / pharmacology*
  • Multiprotein Complexes / antagonists & inhibitors*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • Benzamides
  • Morpholines
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Pyrimidines
  • vistusertib
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2