학술논문
Discovery of Potent, Selective, and Brain-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors that Modulate Brain Inflammation In Vivo
Document Type
Article
Author
Jones, J. Howard; Xin, Zhili; Himmelbauer, Martin; Dechantsreiter, Michael; Enyedy, Istvan; Hedde, Joseph; Fang, Terry; Coomaraswamy, Janaky; King, Kristopher W.; Murugan, Paramasivam; Santoro, Joseph C.; Hesson, Thomas; Walther, Dirk M.; Wei, Ru; Zheng, Fengmei; Marcotte, Douglas J.; Spilker, Kerri; Kumar, P. Rajesh; Liu, Ying; Gilfillan, Rab; Gonzalez-Lopez de Turiso, Felix
Source
Journal of Medicinal Chemistry; October 2021, Vol. 64 Issue: 20 p15402-15419, 18p
Subject
Language
ISSN
00222623; 15204804
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 32to 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.