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

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


Year:
2003
Note:
Applicant(s): Picower inst med res [US]
Other identifiers:
EPO Family ID: 23336711
Patent number(s):
Laboratories:




 Record created 2009-10-29, last modified 2018-03-17

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