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An aminopyridazine-based inhibitor of a pro-apoptotic protein kinase attenuates hypoxia-ischemia induced acute brain injury.

Abstract：

:Death associated protein kinase (DAPK) is a calcium and calmodulin regulated enzyme that functions early in eukaryotic programmed cell death, or apoptosis. To validate DAPK as a potential drug discovery target for acute brain injury, the first small molecule DAPK inhibitor was synthesized and tested in vivo. A single injection of the aminopyridazine-based inhibitor administered 6 h after injury attenuated brain tissue or neuronal biomarker loss measured, respectively, 1 week and 3 days later. Because aminopyridazine is a privileged structure in neuropharmacology, we determined the high-resolution crystal structure of a binary complex between the kinase domain and a molecular fragment of the DAPK inhibitor. The co-crystal structure describes a structural basis for interaction and provides a firm foundation for structure-assisted design of lead compounds with appropriate molecular properties for future drug development.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Velentza AV,Wainwright MS,Zasadzki M,Mirzoeva S,Schumacher AM,Haiech J,Focia PJ,Egli M,Watterson DM

doi

10.1016/s0960-894x(03)00733-9

subject

Has Abstract

pub_date

2003-10-20 00:00:00

pages

3465-70

issue

20

eissn

0960-894X

issn

1464-3405

pii

S0960894X03007339

journal_volume

13

pub_type

杂志文章

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