Discovery of potent, selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors

Bioorg Med Chem Lett. 2013 Feb 15;23(4):979-84. doi: 10.1016/j.bmcl.2012.12.042. Epub 2012 Dec 21.

Abstract

This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure-activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors.

Publication types

  • Letter

MeSH terms

  • Administration, Oral
  • Animals
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • Mice
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrazines / chemistry*
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyrazines
  • Protein-Tyrosine Kinases
  • TNK2 protein, human