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

Andrew M Griffin; Kristopher M Kahlig; Robert John Hatch; Zoë A Hughes; Mark L Chapman; Brett Antonio; Brian E Marron; Marion Wittmann; Gabriel Martinez-Botella

doi:10.1021/acsmedchemlett.0c00675

Discovery of the First Orally Available, Selective K_Na1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series

ACS Med Chem Lett. 2021 Mar 9;12(4):593-602. doi: 10.1021/acsmedchemlett.0c00675. eCollection 2021 Apr 8.

Authors

Andrew M Griffin¹, Kristopher M Kahlig¹, Robert John Hatch^{1

2}, Zoë A Hughes¹, Mark L Chapman³, Brett Antonio³, Brian E Marron¹, Marion Wittmann¹, Gabriel Martinez-Botella¹

Affiliations

¹ Praxis Precision Medicines, Research Innovation, Cambridge, Massachusetts 02142, United States.
² The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3052, Australia.
³ ICAGEN, Durham, North Carolina 27703, United States.

Abstract

The gene KCNT1 encodes the sodium-activated potassium channel K_Na1.1 (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_Na1.1 inhibitors, leading to the discovery of compound 31 that reduced seizures and interictal spikes in a mouse model of KCNT1 GoF.