Discovery of CNS-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors

Zhili Xin; Martin K Himmelbauer; J Howard Jones; Istvan Enyedy; Rab Gilfillan; Thomas Hesson; Kristopher King; Douglas J Marcotte; Paramasivam Murugan; Joseph C Santoro; Felix Gonzalez-Lopez de Turiso

doi:10.1021/acsmedchemlett.9b00611

Discovery of CNS-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors

ACS Med Chem Lett. 2020 Feb 12;11(4):485-490. doi: 10.1021/acsmedchemlett.9b00611. eCollection 2020 Apr 9.

Affiliation

¹ Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is a key mediator in the apoptotic and inflammatory cellular stress response. To investigate the therapeutic value of modulating this pathway in neurological disease, we have completed medicinal chemistry studies to identify novel CNS-penetrant ASK1 inhibitors starting from peripherally restricted compounds reported in the literature. This effort led to the discovery of 21, a novel ASK1 inhibitor with good potency (cell IC₅₀ = 138 nM), low clearance (rat Cl/Cl_u = 0.36/6.7 L h^-1 kg^-1) and good CNS penetration (rat K _p,uu = 0.38).