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

被引：18

作者：

Xin, Zhili ^{[1
]}

Himmelbauer, Martin K. ^{[1
]}

Jones, J. Howard ^{[1
]}

Enyedy, Istvan ^{[1
]}

Gilfillan, Rab ^{[1
]}

Hesson, Thomas ^{[2
]}

King, Kristopher ^{[3
]}

Marcotte, Douglas J. ^{[4
]}

Murugan, Paramasivam ^{[2
]}

Santoro, Joseph C. ^{[2
]}

de Turiso, Felix Gonzalez-Lopez ^{[1
]}

机构：

[1] Biogen, Med Chem, Cambridge, MA 02142 USA

[2] Biogen, Bioassays, Cambridge, MA 02142 USA

[3] Biogen, Drug Metab & Pharmacokinet, Cambridge, MA 02142 USA

[4] Biogen, Phys Biochem & Mol Design, Cambridge, MA 02142 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 04期

关键词：

Apoptosis signal-regulating kinase 1; ASK1; rational design; CNS penetration; neurodegenerative diseases;

D O I：

10.1021/acsmedchemlett.9b00611

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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,K- uu = 0.38).

引用

页码：485 / 490

页数：6

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