Discovery of Potent, Selective, and Brain-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors that Modulate Brain Inflammation <i>In Vivo</i>
J. Howard Jones, Zhili Xin, Martin Himmelbauer, Michael A. Dechantsreiter, Istvan Enyedy, Joseph R. Hedde, Terry Fang, Janaky Coomaraswamy, Kristopher King, Paramasivam Murugan, Joseph C. Santoro, Thomas Hesson, Dirk Walther, Ru Wei, Fengmei Zheng, D.J. Marcotte, Kerri Spilker, P. Rajesh Kumar, Ying Liu, Rab Gilfillan, Felix González-López de Turiso
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 3. This effort led to the discovery of 32, a potent (cell IC50 = 25 nM) and selective ASK1 inhibitor with suitable pharmacokinetic and brain penetration (rat Cl/Clu = 1.6/56 L/h/kg and Kp,uu = 0.46) for proof-of-pharmacology studies. Specifically, the ability of 32 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 32 (at 3, 10, and 30 mg/kg, BID/PO for 4 days) showed a robust reduction of inflammatory markers (e.g., IL-1β) in the cortex, thus confirming inhibition of ASK1 in the CNS.