Agents capable of preventing the misfolding and sequestration of the microtubule-stabilizing protein tau into insoluble fibrillar aggregates hold considerable promise for the prevention and/or treatment of neurodegenerative tauopathies such as Alzheimer’s disease.
Because tauopathies are characterized by amyloidosis that is restricted to the central nervous system (CNS), plausible candidate compounds for in vivo evaluation must both prevent tau fibrillization and achieve significant brain levels.
Recently, we reported the discovery of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors
and now describe a series of new analogues that are both effective inhibitors of tau fibrillization and display significant brain-to-plasma exposure ratios after administration to mice.
Further, two of the most promising examples, 15 and 16, were found to reach significant brain exposure levels following oral administration. Taken together, these results suggest that examples from the ATPZ class hold promise as candidates for in vivo efficacy studies in animal models of neurodegenerative tauopathies.
As a result, bicyclic skeletones might be important, and key is the aromatic amines such as dopamine and L-DOPA could be promissing core pharmacophores for druggable candidates.
返信削除Another Bicyclic candidates must be Rhodanin congeners, which is containing 5-membered imide or thioimide structural motifs, that are oftentimes found as phtalimide and benzrhodanines!!
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