Discovery of CVN293, a Brain Permeable KCNK13 (THIK-1) Inhibitor Suitable for Clinical Assessment
Roland W. Bürli, Kevin Doyle, Louise Dickson, Anna Rowland, Kim L. Matthews, Andrew J. Stott, Martin Teall, Bernardino Ossola, Samuel Russell, Jenna R. M. Harvey, Yiming Wu, Lakshminarayana Narayana, Nicola Brice, Mark Carlton, Lee A. Dawson
Abstract
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.