Methods of modifying amyloid β oligomers using non-peptidic compounds
Disclosed are methods of inhibiting, regulating, and/or modulating the formation of soluble, globular, non-fibrillar, neurotoxic amyloid β 1-42 oligomers from amyloid β 1-42 monomers. Also disclosed are methods of treating a patient suffering from diseases associated with the formation of soluble, globular, non-fibrillar, neurotoxic amyloid β 1-42 oligomers.
1. A method for antagonizing neurotoxic ADDL formation from monomeric Aβ 1-42 by contacting monomeric Aβ 1-42 with an effective amount of a compound selected from the group consisting of
N-(2-Methoxy-phenyl)-2-oxo-2-{N′-[3-oxo-3-thiophen-2-yl-1-trifluoromethyl-prop-(Z)-ylidene]-hydrazino}-acetamide,
2-{[1-(2-Hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester,
2-{[1-(2-Hydroxynaphthalen-1-yl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester,
2-{[1-(2-Hydroxyphenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester,
2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(2-methoxyphenyl)-2-oxoacetamide,
(E)-2-hydroxy-N′-((1-hydroxynaphthalen-2-yl)methylene)benzohydrazide,
or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.
2. The method of claim 1 , wherein the compound is N-(2-Methoxy-phenyl)-2-oxo-2-{N′-[3-oxo-3-thiophen-2-yl-1-trifluoromethyl-prop-(Z)-ylidene]-hydrazino}-acetamide, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.
3. The method of claim 1 , wherein the compound is 2-{[1-(2-Hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.
4. The method of claim 1 , wherein the compound is N-(2-Methoxy-phenyl)-2-{[1-(2-Hydroxynaphthalen-1-yl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.
5. The method of claim 1 , wherein the compound is N-(2-Methoxy-phenyl)-2-{[1-(2-Hydroxyphenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.
6. The method of claim 1 , wherein the compound is N-(2-Methoxy-phenyl)-2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(2-methoxyphenyl)-2-oxoacetamide, or a stcreoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.
7. The method of claim 1 , wherein the compound is N-(2-Methoxy-phenyl)-(E)-2-hydroxy-N-((1-hydroxynaphthalen-2-yl)methylene)benzohydrazide, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.