Compounds for inhibiting beta-amyloid production and methods of identifying the compounds

A method for treating a disease associated with cerebral accumulation of Alzheimer amyloid, comprising administering to an animal or human a therapeutically effective amount of a compound that decreases capacitative calcium entry by at least about 10% or more in cells which optionally overexpress APP or a fragment thereof, wherein the compound is a dihydropyridine which is optionally other than nilvadipine, nimodipine or nitrendipine or a salt, or free base thereof;

• an imidazole compound;
• an isoquinoline alkaloid compound;
• a calmodulin-mediated enzyme activation inhibitor;
• an inhibitor of kinase activity of the platelet-derived growth factor (PDGF) receptor;
• an NF-kB activation inhibitor;
• a diterpene or triterpene compound;
• a quinazoline compound;
• a sesquiterpene lactone;
• or an inhibitor of IKK-2.

A method for treating a disease associated with cerebral accumulation of Alzheimer amyloid, comprising administering to an animal or human a therapeutically effective amount of a compound that decreases capacitative calcium entry by at least about 10% or more in cells which optionally overexpress APP or a fragment thereof, wherein the compound is a compound of Formula I, or a salt, ester or prodrug thereof, or an R or S isomer thereof:

• wherein:
• R1 is H, alkyl, optionally substituted aryl, optionally substituted heterocycle, alkyl or aryl ether;
• R2 and R6 are independently alkyl, alkyl ether, aryl ether, halogen, or hydroxy;
• R3 and R5 are independently optionally substituted alkyl ester, aryl ester, silyl ester, alkyl amide, aryl amide, cyano, or nitro;
• R2′ and R6′ are independently H, alkyl, optionally substituted alkyl ether, optionally substituted aryl ether, halogen, hydroxy, nitro, carboxylic acid, boronic acid, haloalkyl, amine, optionally substituted alkyl amine, nitrile, optionally substituted alkyl thioether, optionally substituted aryl thioether, or optionally substituted heterocycle;
• R3′ and R5′ are independently H, alkyl, optionally substituted alkyl ether, optionally substituted aryl ether, halogen, hydroxy, nitro, carboxylic acid, boronic acid, haloalkyl, amine, optionally substituted alkyl amine, nitrile, optionally substituted alkyl thioether, optionally substituted aryl thioether, or optionally substituted heterocycle;
• R4′ is independently H, alkyl, optionally substituted alkyl ether, optionally substituted aryl ether, halogen, hydroxy, nitro, carboxylic acid, boronic acid, haloalkyl, amine, optionally substituted alkyl amine, nitrile, optionally substituted alkyl thioether, optionally substituted aryl thioether, or optionally substituted heterocycle;
• or R2′ and R3′ together can optionally form a 4, 5, 6 or 7 membered heterocycle containing 1, 2, or 3 heteroatoms and can be optionally substituted with alkyl, optionally substituted alkyl ether, optionally substituted aryl ether, halogen, hydroxy, nitro, carboxylic acid, boronic acid, haloalkyl, amine, optionally substituted alkyl amine, nitrile, optionally substituted alkyl thioether, optionally substituted aryl thioether, or optionally substituted heterocycle;
• or R3′ and R4′ together can optionally form a 4, 5, 6 or 7 membered heterocycle containing 1, 2, or 3 heteroatoms and can be optionally substituted with alkyl, optionally substituted alkyl ether, optionally substituted aryl ether, halogen, hydroxy, nitro, carboxylic acid, boronic acid, haloalkyl, amine, optionally substituted alkyl amine, nitrile, optionally substituted alkyl thioether, optionally substituted aryl thioether, or optionally substituted heterocycle;
• or R4′ and R5′ together can optionally form a 4, 5, 6 or 7 membered heterocycle containing 1, 2, or 3 heteroatoms and can be optionally substituted with alkyl, optionally substituted alkyl ether, optionally substituted aryl ether, halogen, hydroxy, nitro, carboxylic acid, boronic acid, haloalkyl, amine, optionally substituted alkyl amine, nitrile, optionally substituted alkyl thioether, optionally substituted aryl thioether, or optionally substituted heterocycle;
• or R5′ and R6′ together can optionally form a 4, 5, 6 or 7 membered heterocycle containing 1, 2, or 3 heteroatoms and can be optionally substituted with alkyl, optionally substituted alkyl ether, optionally substituted aryl ether, halogen, hydroxy, nitro, carboxylic acid, boronic acid, haloalkyl, amine, optionally substituted alkyl amine, nitrile, optionally substituted alkyl thioether, optionally substituted aryl thioether, or optionally substituted heterocycle.

A method for treating a disease associated with cerebral accumulation of Alzheimer amyloid, comprising administering to an animal or human a therapeutically effective amount of a compound that decreases capacitative calcium entry by at least about 10% or more in cells which optionally overexpress APP or a fragment thereof, wherein the compound is a compound of formula VI, or a salt, ester or prodrug there of, or an R or S isomer thereof:

• wherein:
• R1 is C3-12 alkyl, and is optionally cycloalkyl, cyclohexyl or cyclopentyl;
• R2 and R4 are independently H or halo;
• and
• R3 is unsubstituted phenyl or phenyl optionally substituted with one or more halo or hydroxy groups.