Discovery of 2-arylamino-4-(1-methyl-3-isopropylsulfonyl-4-pyrazol-amino)pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3738-43. doi: 10.1016/j.bmcl.2015.06.021. Epub 2015 Jun 16.

Abstract

A new series of 2,4-diamino pyrimidine derivatives with a sulfone-substituted pyrazole right side-chain were discovered as potent anaplastic lymphoma kinase inhibitors. Structure-activity relationship of the left side-chain on phenyl substitutions were explored which delivered many potent ALK inhibitors. Among them, 29a showed favorable pharmacokinetic profiles in rats and dogs together with significant antitumor efficacy in EML4-ALK fusion xenograft model.

Keywords: ALK; Antitumor efficacy; Kinase inhibitor; NSCLC; PK properties.

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Biological Availability
  • Chemistry Techniques, Synthetic
  • Dogs
  • Drug Design
  • Drug Discovery
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Oncogene Proteins, Fusion / genetics
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • EML4-ALK fusion protein, human
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Pyrimidines
  • ALK protein, human
  • Alk protein, mouse
  • Alk protein, rat
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases