ABSTRACT
Glycogen synthase kinase-3ß, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3ß localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyrazines/chemical synthesis , 3T3 Cells , Animals , Blood-Brain Barrier/metabolism , Caco-2 Cells , Cattle , Crystallography, X-Ray , Drug Design , Glycogen Synthase Kinase 3 beta , Humans , Mice , Models, Molecular , Molecular Structure , Permeability , Phosphorylation , Pyrazines/chemistry , Pyrazines/pharmacology , Solubility , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology , tau Proteins/metabolismABSTRACT
The structure-based design and synthesis of a new series of c-Jun N-terminal kinase-3 inhibitors with selectivity against JNK1 and p38alpha is reported. The novel series of substituted 6-anilinoindazoles were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of the compounds crystallized into the JNK3 ATP binding active site.
