Discovery of the First Orally Available, Selective KNa1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series

The gene KCNT1 encodes the sodium-activated potassium channel KNa1.1 (Slack, Slo2.2). Variants in the KCNT1 gene induce a gain-of-function (GoF) phenotype in ionic currents and cause a spectrum of intractable neurological disorders in infants and children, including epilepsy of infancy with migratin...

Full description

Saved in:
Bibliographic Details
Published in:ACS medicinal chemistry letters 2021-04, Vol.12 (4), p.593-602
Main Authors: Griffin, Andrew M, Kahlig, Kristopher M, Hatch, Robert John, Hughes, Zoë A, Chapman, Mark L, Antonio, Brett, Marron, Brian E, Wittmann, Marion, Martinez-Botella, Gabriel
Format: Article
Language:English
Subjects:
Letter
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The gene KCNT1 encodes the sodium-activated potassium channel KNa1.1 (Slack, Slo2.2). Variants in the KCNT1 gene induce a gain-of-function (GoF) phenotype in ionic currents and cause a spectrum of intractable neurological disorders in infants and children, including epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Effective treatment options for KCNT1-related disease are absent, and novel therapies are urgently required. We describe the development of a novel class of oxadiazole KNa1.1 inhibitors, leading to the discovery of compound 31 that reduced seizures and interictal spikes in a mouse model of KCNT1 GoF.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.0c00675