David R Callaway

US Patent:

20080096909, Apr 24, 2008

Filed:

Apr 20, 2007

Appl. No.:

11/738162

Inventors:

Hilal Lashuel - Everett MA, US
David Callaway - New York NY, US

Assignee:

CYTOKINE PHARMASCIENCES, INC. - King of Prussia PA

International Classification:

A61K 31/473
A61P 43/00

US Classification:

514284000

Abstract:

Described is a new class of small molecule inhibitors of amyloid β protein (Aβ) aggregation, based on apomorphine. These molecules target the nucleation phase of Aβ self-assembly and interfere effectively with aggregation of Aβ 1-40 into amyloid fibrils in vitro 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 Aβ 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 Aβ into short nonfibrillar soluble assemblies, but inhibit Aβ fibrillization.

US Patent:

20030187011, Oct 2, 2003

Filed:

Dec 17, 2002

Appl. No.:

10/320609

Inventors:

Hilal Lashuel - Everett MA, US
David Callaway - New York NY, US

International Classification:

A61K031/473

US Classification:

514/284000

Abstract:

Described is a new class of small molecule inhibitors of amyloid protein (A) aggregation, based on apomorphine. These molecules target the nucleation phase of A self-assembly and interfere effectively with aggregation of A 1-40 into amyloid fibrils in vitro 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 A amyloid fibril formation appears to be linked to their ability to undergo auto-oxidation in solution, implicating an auto-oxidation product as the active A inhibitor. Sedimentation velocity and electron microscopy studies demonstrate that apomorphine and analogues facilitate oligomerization of A into short nonfibrillar soluble assemblies, but inhibit A fibrillization.