Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model

J Med Chem. 2018 Dec 27;61(24):11398-11414. doi: 10.1021/acs.jmedchem.8b01652. Epub 2018 Dec 10.


We herein report the structural optimization and structure-activity relationship studies of 5-(2,3-dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine derivatives as a new class of receptor-interacting protein kinase 1 (RIPK1) inhibitors. Among all obtained RIPK1 inhibitors, 1-(5-{4-amino-7-ethyl-7 H-pyrrolo[2,3- d]pyrimidin-5-yl}-2,3-dihydro-1 H-indol-1-yl)-2-[3-(trifluoromethoxy)phenyl]ethan-1-one (22b) is the most active one. This compound potently inhibited RIPK1 with a binding affinity ( KD) of 0.004 μM and an enzymatic IC50 value of 0.011 μM and also showed good kinase selectivity. It could efficiently protect cells from necroptosis and attenuate the necrotic cell death of vascular endothelial cells induced by tumor cells both in vitro and in vivo. Importantly, compound 22b exhibited excellent antimetastasis activity in the experimental B16 melanoma lung metastasis model. It also displayed favorable pharmacokinetic properties. Collectively, 22b could be a promising agent for preventing tumor metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • HT29 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / secondary*
  • Male
  • Melanoma / pathology
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism
  • Rats, Sprague-Dawley
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • MLKL protein, human
  • Protein Kinases
  • RIPK1 protein, human
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases