Malignant Migrating Partial Seizures of Infancy (MMPSI) is a severe, drug resistant, and often fatal disease. Slack channels, encoded by the KCNT1 gene, are sodium-activated potassium channels that regulate essential electrical activity in the central nervous system. Approximately 30 gain-of-function mutations in Slack channels are associated with a variety of epilepsies, most frequently MMPSI. Drugs that can inhibit the activity of mutant Slack channels may provide effective treatments for MMPSI and other epilepsies. The objective of our work is to develop selective small molecule inhibitors of Slack as leads for development of MMPSI therapeutics employing a library synthesis based, iterative hit optimization approach. The hit compound VU0606170, an inhibitor of Slack Channels (Figure 1), was identified via High-throughput Screening (HTS) utilizing a thallium (Tl+) flux assay and cells stably expressing wild-type and MMPSI-associated, mutant Slack channels. VU0606170 has multiple regions amenable to rapid SAR development through the preparation of small libraries of compounds. SAR studies around hit compound VU0606170 identified a chiral-methyl analog in the piperizine core as optimal for potency while modifications to linker B did not improve potency. Certain isosteric core analogs were effective but less potent than their piperazine counterparts. Several urea and amide analogs were prepared at linker A, and a few moderately potent compounds were identified. Replacement of the sulfamide linkers with a sulfonamide gave potent compounds in some cases. Second- and third-generation libraries were prepared that combined optimal functional groups from across the chemotype with a goal of improving potency and/or DMPK properties. Lastly, in-vitro DMPK studies with selected compounds generally revealed high clearance, high protein binding, and good membrane permeability within the series.

Discovery of small molecule slack inhibitors for the treatment of MMPSI: SAR studies around HTS hit compound VU0606170

ACS Spring Meeting 2021

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