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

doi:10.1021/acsmedchemlett.8b00591

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

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	627-632
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	4
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00591
Publication status	Published - Apr 11 2019

Keywords

ASICs
cancer
CNS
drug discovery
ion channels
PNS

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.8b00591

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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

Bencheva, LI, 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, vol. 10, no. 4, pp. 627-632. https://doi.org/10.1021/acsmedchemlett.8b00591

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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.",

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AU - Ferrara, Marco

AU - Prandi, Adolfo

AU - Randazzo, Pietro

AU - Ronzoni, Silvano

AU - Sinisi, Roberta

AU - Seneci, Pierfausto

AU - Summa, Vincenzo

AU - Gallo, Mariana

AU - Veneziano, Maria

AU - Cellucci, Antonella

AU - Mazzocchi, Nausicaa

AU - Menegon, Andrea

AU - Di Fabio, Romano

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

Abstract

Keywords

ASJC Scopus subject areas

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