Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[ d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases

J Med Chem. 2019 Jul 25;62(14):6482-6494. doi: 10.1021/acs.jmedchem.9b00575. Epub 2019 Jul 2.

Abstract

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.

MeSH terms

  • Animals
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacokinetics
  • Benzothiazoles / pharmacology*
  • Benzothiazoles / therapeutic use
  • Colitis / drug therapy
  • Dogs
  • Drug Discovery
  • Humans
  • Male
  • Mice
  • Molecular Docking Simulation
  • Phosphates / chemistry
  • Phosphates / pharmacokinetics
  • Phosphates / pharmacology*
  • Phosphates / therapeutic use
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Quinazolines / chemistry
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Rats, Sprague-Dawley
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / antagonists & inhibitors*
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
  • Swine
  • Swine, Miniature

Substances

  • Benzothiazoles
  • Phosphates
  • Protein Kinase Inhibitors
  • Quinazolines
  • ethyl dihydrogen phosphate
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2