# Optimization of Novel Potassium Channel Kv1.3 Blockers with Potential as Alzheimer's Disease Therapeutics

> **NIH NIH R43** · HAGER BIOSCIENCES, LLC · 2024 · $499,968

## Abstract

Abstract (Project Summary)
Alzheimer's Disease (AD) is one of the major neurodegenerative disorders and leading cause of dementia, mostly
prevalent in the aging population. Aging-associated impairments and cognitive decline due to AD and other
neurodegenerative disorders severely affect the quality-of-life for elders and add significantly to related
socioeconomic costs, which in the U.S. was estimated to total over $655 billion in 2020. Chronic systemic
inflammation is an underlying driver for several disease states including cancer, autoimmune disorders, and
cardiovascular disease. Neuroinflammation, defined as an inflammatory response in the brain, spinal cord, glia, or
other neuronal tissue, contributes significantly to neurodegenerative signaling cascades which underlie AD and
other diseases such as FTLD, PD, HD, MS, ALS, and TBI. Particularly in AD, initial neuroinflammatory response
(M2 phenotype) develops as a defense mechanism within the CNS to rid itself of diverse noxious agents, cellular
debris, and misfolded proteins such as Tau and Aβ. Despite their intended roles to attenuate tissue injury, cellular
inflammatory processes in the CNS that become chronic and uncontrolled (M1 phenotype) inhibit regeneration and
promote neurodegeneration. Overactivation of Kv1.3, a member of the super family of voltage-gated potassium
channels, is heavily implicated in tipping the M1 (classical activation) / M2 (alternative activation) phenotype
expression in microglia from a balanced steady-state (good neuronal health) to predominately the M1 phenotype
mode of microglial activation associated with AD. Both peptidic and small molecule inhibitors of Kv1.3 have shown
efficacy in numerous animal models of AD, but their further development has been hampered by poor drug-like
properties. As such, using a fragment based pharmacophore analysis and design, Hager Biosciences has
discovered differentiated scaffold classes small molecule Kv1.3 channel blockers which showed potent inhibitions
in CHO cells stably expressing h Kv1.3 using electrophysiological whole-cell voltage-clamp format. Therefore, the
goal of this project is to further develop these compounds as innovative potential treatments for AD. Thus, the 1st
Specific Aim is to (a) complete the in vitro characterization of analog leads by generating Kv1.3 inhibitory IC50 values
for compounds inhibiting Kv1.3 >50% at 1 uM - using whole cell voltage-clamp protocol, and (b) select representative
leads for initial pharmaceutical profiling assays (solubility, permeability, microsomal stability, protein binding, and
efflux ratio). The 2nd Specific Aim is to (a) initiate iterative multi-parameter lead optimization campaign to improve
target potency and ADMET properties based on 2-4 structural classes which provided compounds with optimal
overall profiles emerging from Specific Aim 1; and (b) select representative leads possessing inhibitory Kv1.3 IC50
values < 100 nM and perform selectivity screen against Kv1.4, ...

## Key facts

- **NIH application ID:** 10920282
- **Project number:** 1R43AG085864-01A1
- **Recipient organization:** HAGER BIOSCIENCES, LLC
- **Principal Investigator:** John A Butera
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $499,968
- **Award type:** 1
- **Project period:** 2024-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10920282

## Citation

> US National Institutes of Health, RePORTER application 10920282, Optimization of Novel Potassium Channel Kv1.3 Blockers with Potential as Alzheimer's Disease Therapeutics (1R43AG085864-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10920282. Licensed CC0.

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