Journal
CURRENT ALZHEIMER RESEARCH
Volume 13, Issue 12, Pages 1330-1336Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205013666160615091821
Keywords
Multitargeted approach; substituent effects; kinase inhibition; tau protein; enzyme binding; total tau
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Funding
- DFG (Deutsche Forschungsgemeinschaft) [HI 687/8-1, HO 2368/4-1, SI 868/6-1]
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So far monotargeted therapies in Alzheimers disease (AD) led to insufficient results. Slight improvements in the AD symptomatics have been limited to patients in the early stage of the disease. So multitargeting approaches have been started addressing amyloid plaques as preferred primary target structures beside acetylcholine esterase inhibition. Various protein kinases have been discussed to make a contribution to the progression of AD. So protein kinases are promising target structures for a perspective multitargeting. We identified substituted small-molecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3 beta, extracellular-signal regulated kinase (ERK) 2 and C-Jun-N-terminal kinase (JNK) 3. Substituent-dependent effects on the respective kinase inhibitions are discussed and inhibitor binding modes to those kinases are presented based on enzyme docking studies. Inhibitor effects on the tau protein target structure are shown for first compounds in cellular studies to prove the enzyme conditioned effects.
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