Apomorphine inhibitors of amyloid-beta (abeta) fibril formation and their use in amyloidosis based disease

• Publication date: 2003

Described is a new class of small molecule inhibitors of amyloid beta protein (Abeta) aggregation, based on apomorphine. These molecules target the nucleation phase of Abeta self-assembly and interfere effectively with aggregation of Abeta 1-40 into amyloid fibrils invitro as determined by transmission electron microscopy, Thioflavin T (ThT) fluorescence, and velocity sedimentation. Structure-activity studies using apomorphine analogues demonstrate that 10, 11-dihydroxy substitutions of the D ring are preferred for the inhibitory effectiveness of these aporphines, and that methylation of these hydroxyl groups reduces their inhibitory potency. The ability of these small molecules to inhibit Abeta amyloid fibril formation appears to be linked to their ability to undergo auto-oxidation in solution, implicating an auto-oxidation product as the active Aβ, inhibitor.; Sedimentation velocity and electron microscopy studies demonstrate that apomorphine and analogues facilitate oligomerization of Abeta into short nonfibrillar soluble assemblies, but inhibit Abeta fibrilization

• Patent numbers:
  • CA2479263 (A1)
  • WO03053356

Note:

Applicant(s): Picower inst med res [US]

Reference

• LMNN-PATENT-2009-002
• Search for this record at the European Patent Office

Record created on 2009-10-29, modified on 2017-05-12