Tricyclic pyrone compounds reduce amyloid beta aggregates
AssigneesKansas State University Research Foundation, The Regents of the University of California, a California corporation, Afasci, Inc.
InventorsDuy H Hua, Lee-way Jin, Izumi Maezawa, Xinmin Xie
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Abstract
Tricyclic pyrone compounds having high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity are presented. Administration of the compounds to Alzheimer's Disease transgenic models resulted in substantially reduced soluble and insoluble Aβ species in the brain without affecting general behavior and motor coordination. Furthermore, in addition to blocking the toxicity and formation of both intraneuronal and extracellular Aβ aggregates, the compounds also increase cellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic plasticity.
Claims7
A method for reducing cerebral amyloid load and toxic Ab dimer level in a subject in need thereof, comprising orally administering to said subject a therapeutically effective amount of a compound of the formula
- wherein,
- R1, R2, and R3 are independently selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
- and
- R4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
- wherein R4 is other than adenine joined to the remainder of the compound through an endocyclic nitrogen atom of said adenine,
- wherein said therapeutically effective amount is sufficient to achieve therapeutic brain concentration of said compound and reduce cerebral amyloid load and toxic Aβ dimer level, and said compound protects MC65 neuroblastoma cells from death caused by Aβ in a medium-throughput cell-based MC65 protection assay.
Dependencies are inferred from the claim text.