Open AccessDiscovery of CNS-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors
Author(s) -
Zhili Xin,
Martin K Himmelbauer,
John Howard Jones,
Istvan Enyedy,
Rab Gilfillan,
Thomas Hesson,
Kristopher King,
D.J. Marcotte,
M. Paramasivam,
Joseph C. Santoro,
Felix González-López de Turiso
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00611
Subject(s) - ask1 , apoptosis , penetrant (biochemical) , pharmacology , kinase , mediator , signal transduction , xiap , protein kinase a , medicine , chemistry , cancer research , neuroscience , biology , microbiology and biotechnology , programmed cell death , biochemistry , mitogen activated protein kinase kinase , caspase , organic chemistry
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 IC 50 = 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).