2. Academic Validation
  3. Discovery of Potent, Selective, and Brain-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors that Modulate Brain Inflammation In Vivo

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

  • J Med Chem. 2021 Oct 28;64(20):15402-15419. doi: 10.1021/acs.jmedchem.1c01458.
J Howard Jones 1,  Zhili Xin 1,  Martin Himmelbauer 1,  Michael Dechantsreiter 1,  Istvan Enyedy 1,  Joseph Hedde 2,  Terry Fang 2,  Janaky Coomaraswamy 3,  Kristopher W King 4,  Paramasivam Murugan 5,  Joseph C Santoro 5,  Thomas Hesson 5,  Dirk M Walther 6,  Ru Wei 6,  Fengmei Zheng 7,  Douglas J Marcotte 8,  Kerri Spilker 8,  P Rajesh Kumar 8,  Ying Liu 4,  Rab Gilfillan 1,  Felix Gonzalez-Lopez de Turiso 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 2 Acute Neurology Research Unit, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 3 Movement Disorders Research Unit, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 4 Drug Metabolism and Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 5 Bioassays, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 6 Chemical Biology and Proteomics, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 7 Technical Development, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 8 Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
PMID: 34653340 DOI: 10.1021/acs.jmedchem.1c01458
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.

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