Open AccessDiscovery of the First Orally Available, Selective KNa1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series
Author(s) -
Andrew M. Griffin,
Kristopher M. Kahlig,
Robert J. Hatch,
Zoë A. Hughes,
Mark L. Chapman,
Brett Antonio,
Brian E. Marron,
Marion Wittmann,
Gabriel Martínez-Botella
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00675
Subject(s) - in vivo , ictal , epilepsy , phenotype , medicine , oxadiazole , pharmacology , bioinformatics , neuroscience , biology , gene , chemistry , genetics , organic chemistry
The gene KCNT1 encodes the sodium-activated potassium channel K Na 1.1 (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 K Na 1.1 inhibitors, leading to the discovery of compound 31 that reduced seizures and interictal spikes in a mouse model of KCNT1 GoF.