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.

• Authors: Anastasia V Velentza, Mark S Wainwright, Magdalena Zasadzki, Salida Mirzoeva, Andrew M Schumacher, Jacques Haiech, Pamela J Focia, Martin Egli, D Martin Watterson
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 13 Issue 20 Pg. 3465-70 (Oct 20 2003) ISSN: 0960-894X [Print] England
• PMID: 14505650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apoptosis Regulatory Proteins
• Enzyme Inhibitors
• Pyridazines
• pyridazine
• Death-Associated Protein Kinases
• Calcium-Calmodulin-Dependent Protein Kinases

Topics

• Animals
• Apoptosis
• Apoptosis Regulatory Proteins
• Brain Injuries (etiology, prevention & control)
• Calcium-Calmodulin-Dependent Protein Kinases (antagonists & inhibitors)
• Death-Associated Protein Kinases
• Enzyme Inhibitors (chemistry, pharmacology)
• Hypoxia-Ischemia, Brain (complications, prevention & control)
• Mice
• Pyridazines (chemistry, pharmacology)