Discovery of CVN293, a Brain Permeable KCNK13 (THIK-1) Inhibitor Suitable for Clinical Assessment.
Roland W BürliKevin J DoyleLouise DicksonAnna RowlandKim MatthewsAndrew J StottMartin TeallBernardino OssolaSamuel G RussellJenna R M HarveyYiming WuLakshminarayana NarayanaNicola L BriceMark CarltonLee A DawsonPublished in: ACS medicinal chemistry letters (2024)
The potassium (K + ) ion channel KCNK13 is specifically expressed in human microglia with elevated expression observed in post-mortem human brain tissue from patients with Alzheimer's disease. Modulation of KCNK13 activity by a small-molecule inhibitor is proposed as a potential treatment for neurodegenerative diseases. Herein, we describe the evolution of a series of KCNK13 inhibitors derived from a high-throughput screening campaign, resulting in CVN293 , a potent, selective, and brain permeable clinical candidate molecule. CVN293 demonstrated a concentration-dependent inhibition of the NLRP3-inflammasome mediated production of IL-1β from LPS-primed murine microglia. Cross-species pharmacokinetic data of CVN293 are also disclosed. These findings support the advancement of CVN293 in clinical trials.
Keyphrases
- small molecule
- nlrp inflammasome
- inflammatory response
- clinical trial
- resting state
- white matter
- endothelial cells
- poor prognosis
- neuropathic pain
- functional connectivity
- electronic health record
- protein protein
- randomized controlled trial
- high throughput
- risk assessment
- induced pluripotent stem cells
- study protocol
- long non coding rna
- human health
- pluripotent stem cells
- replacement therapy
- genetic diversity