剂阿尔茨海默氏病相关激酶小分子抑制剂作为新颖视角的多靶点药物开发方法的药物发展

Title:Drug Development of Small-Molecule Inhibitors of AD-Relevant Kinases as Novel Perspective Multitargeted Approach

Volume: 13 Issue: 12

Author(s): V. Tell, I. Hilbrich, M. Holzer, Frank Totzke, Christoph Schachtele, Inna Slynko, Wolfgang Sippl, A. Hilgeroth

Affiliation:

关键词: 多方法，取代基效应、激酶抑制tau蛋白，酶结合，总tau蛋白。

摘要: 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 smallmolecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3β, 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.

Cite this article as:

V. Tell, I. Hilbrich, M. Holzer, Frank Totzke, Christoph Schachtele, Inna Slynko, Wolfgang Sippl, A. Hilgeroth , Drug Development of Small-Molecule Inhibitors of AD-Relevant Kinases as Novel Perspective Multitargeted Approach, Current Alzheimer Research 2016; 13 (12) . https://dx.doi.org/10.2174/1567205013666160615091821