Imidazo[1,5-a]pyrazines: orally efficacious inhibitors of mTORC1 and mTORC2

Bioorg Med Chem Lett. 2011 Apr 1;21(7):2092-7. doi: 10.1016/j.bmcl.2011.01.139. Epub 2011 Feb 3.

Abstract

The discovery and optimization of a series of imidazo[1,5-a]pyrazine inhibitors of mTOR is described. HTS hits were optimized for potency, selectivity and metabolic stability to provide the orally bioavailable proof of concept compound 4c that demonstrated target inhibition in vivo and concomitant inhibition of tumor growth in an MDA-MB-231 xenograft model.

MeSH terms

  • Administration, Oral
  • Cell Line, Tumor
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Mechanistic Target of Rapamycin Complex 1
  • Models, Molecular
  • Multiprotein Complexes
  • Proteins / antagonists & inhibitors*
  • Pyrazines / administration & dosage
  • Pyrazines / pharmacology*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • CRTC2 protein, human
  • Imidazoles
  • Multiprotein Complexes
  • Proteins
  • Pyrazines
  • Transcription Factors
  • imidazo(1,5-a)pyrazine
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases