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.

Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS / 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.. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:4(2019), pp. 627-632. [10.1021/acsmedchemlett.8b00591]

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

Gallo M.;
2019-01-01

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.
2019
Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS / 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.. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:4(2019), pp. 627-632. [10.1021/acsmedchemlett.8b00591]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2878176
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