Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1597-602. doi: 10.1016/j.bmcl.2015.02.002. Epub 2015 Feb 16.

Abstract

In a high-throughput screening campaign for c-Met kinase inhibitors, a thiadiazinone derivative with a carbamate group was identified as a potent in vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray structures furnished new compound classes with excellent in vitro and in vivo profiles. The thiadiazinone ring of the HTS hit was first replaced by a pyridazinone followed by an exchange of the carbamate hinge binder with a 1,5-disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119), with excellent in vitro potency, high kinase selectivity, long half-life after oral administration and in vivo anti-tumor efficacy at low doses, was selected as a candidate for clinical development.

Keywords: MSC2156119; Pyridazinone; Structure-based design; Tyrosine kinase; c-Met.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyridazines
  • Proto-Oncogene Proteins c-met