Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2

J Med Chem. 2015 Mar 12;58(5):2326-49. doi: 10.1021/jm501778s. Epub 2015 Feb 18.

Abstract

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

MeSH terms

  • Cells, Cultured
  • Drug Discovery*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Models, Molecular
  • Molecular Structure
  • Multiprotein Complexes / antagonists & inhibitors*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Thiourea / analogs & derivatives*
  • Thiourea / chemistry
  • Thiourea / pharmacology

Substances

  • 1-(4-(4-(1-cyclopropylsulfonylcyclopropyl)-6-(3-methylmorpholin-4-yl)pyrimidin-2-yl)phenyl)-3-(2-hydroxyethyl)thiourea
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Pyrimidines
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Thiourea