Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group

Bioorg Med Chem Lett. 2019 Jun 15;29(12):1497-1501. doi: 10.1016/j.bmcl.2019.04.014. Epub 2019 Apr 11.

Abstract

Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.

Keywords: Metabolic stability; Necroptosis; Pentafluoroethyl; RIPK1; RIPK1 inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Necrosis
  • Protein Kinases / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Protein Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases