Identification of small-molecule urea derivatives as PTPC modulators targeting the c subunit of F1/Fo-ATP synthase

Bioorg Med Chem Lett. 2022 Sep 15:72:128822. doi: 10.1016/j.bmcl.2022.128822. Epub 2022 May 27.

Abstract

Maintaining a high percentage of living and functional cells in those pathologies in which excessive cell death occurs, such as neurodegenerative disorders and cardiovascular diseases, is one of the most intriguing challenges in the field of biochemical research for drug discovery. Here, mitochondrial permeability transition-driven regulated cell death is the main mechanism of mitochondrial impairment and cell fate; this pathway is still lacking of satisfying pharmacological treatments to counteract its becoming; for this reason, it needs continuous and intense research to find new compounds as modulator of the permeability transition pore complex (PTPC) activity. In this study, we report the identification of small-molecule urea derivatives able to inhibit PTPC opening following calcium overload and selected for future use in cytoprotection.

Keywords: Cardiovascular diseases; Mitochondria; PTPC; Urea derivatives.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Azirines
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins* / chemistry
  • Mitochondrial Membrane Transport Proteins* / metabolism
  • Phosphatidylcholines
  • Urea* / metabolism
  • Urea* / pharmacology

Substances

  • Azirines
  • Mitochondrial Membrane Transport Proteins
  • Phosphatidylcholines
  • 1-palmitoyl-2-(10-(4-((trifluoromethyl)diazirinyl)phenyl)-8-oxadecanoyl)-sn-glycero-3-phosphocholine
  • Adenosine Triphosphate
  • Urea