Discovery of Potent, Selective, and Brain-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors that Modulate Brain Inflammation <i>In Vivo</i>

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is one of the key mediators of the cellular stress response that regulates inflammation and apoptosis. To probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, we further optimized the profile of our previously reported inhibitor <b>3</b>. This effort led to the discovery of <b>32</b>, a potent (cell IC₅₀ = 25 nM) and selective ASK1 inhibitor with suitable pharmacokinetic and brain penetration (rat Cl/Cl_u = 1.6/56 L/h/kg and <i>K</i>_p,uu = 0.46) for proof-of-pharmacology studies. Specifically, the ability of <b>32</b> to inhibit ASK1 in the central nervous system (CNS) was evaluated in a human tau transgenic (Tg4510) mouse model exhibiting elevated brain inflammation. In this study, transgenic animals treated with <b>32</b> (at 3, 10, and 30 mg/kg, BID/PO for 4 days) showed a robust reduction of inflammatory markers (<i>e.g.</i>, IL-1β) in the cortex, thus confirming inhibition of ASK1 in the CNS.