Discovery of a highly potent orally bioavailable imidazo-[1, 2-a]pyrazine Aurora inhibitor

Bioorg Med Chem Lett. 2018 May 1;28(8):1397-1403. doi: 10.1016/j.bmcl.2018.02.037. Epub 2018 Feb 23.

Abstract

Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.

Keywords: Aurora inhibitor; Imidazopyrazine; Kinase inhibitor.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase B / antagonists & inhibitors*
  • Dogs
  • HCT116 Cells
  • Haplorhini
  • Histones / metabolism
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacokinetics
  • Imidazoles / therapeutic use*
  • Mice
  • Phosphorylation
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazines / administration & dosage
  • Pyrazines / chemical synthesis
  • Pyrazines / pharmacokinetics
  • Pyrazines / therapeutic use*
  • Rats
  • Stereoisomerism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Histones
  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyrazines
  • Aurora Kinase A
  • Aurora Kinase B