Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS

Leda Ivanova Bencheva, Marilenia De Matteo, Luca Ferrante, Marco Ferrara, Adolfo Prandi, Pietro Randazzo, Silvano Ronzoni, Roberta Sinisi, Pierfausto Seneci, Vincenzo Summa, Mariana Gallo, Maria Veneziano, Antonella Cellucci, Nausicaa Mazzocchi, Andrea Menegon, Romano Di Fabio

Research output: Contribution to journalArticle

Abstract

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies.

Original languageEnglish
Pages (from-to)627-632
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 11 2019

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Keywords

  • ASICs
  • cancer
  • CNS
  • drug discovery
  • ion channels
  • PNS

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Bencheva, L. I., De Matteo, M., Ferrante, L., Ferrara, M., Prandi, A., Randazzo, P., Ronzoni, S., Sinisi, R., Seneci, P., Summa, V., Gallo, M., Veneziano, M., Cellucci, A., Mazzocchi, N., Menegon, A., & Di Fabio, R. (2019). Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS. ACS Medicinal Chemistry Letters, 10(4), 627-632. https://doi.org/10.1021/acsmedchemlett.8b00591