Agents useful for reducing amyloid precursor protein and treating demantia and methods of use thereof

A compound comprising the formula II

• wherein R1 and R2 are, independently, hydrogen, branched or straight chain C1–C8 alkyl, substituted or unsubstituted aryl, or aralkyl;
• R3 is branched or straight chain C1–C4 alkyl or heteroalkyl or C4–C8 alkyl or heteroakyl, or substituted or unsubstituted aryl;
• X is O, S, alkyl, hydrocarbon moiety, C(H)R4, or NR5, wherein R4 and R5 are, independently, hydrogen, oxygen, branched or straight chain C1–C8 alkyl, C2–C8 alkenyl, or C2–C8 alkynyl, aralkyl, or substituted or unsubstituted aryl;
• and wherein,
• R6 is hydrogen;
• C1–C8 alkyl, C2–C8 alkenyl, C2–C8 alkynyl, aralkyl, or substituted or unsubstituted aryl, or (CH2)nR7, where R7 is hydroxy, alkoxy, cyano, ester, carboxylic acid, substituted or unsubstituted amino, and n is from 1 to 4, wherein the compound having the formula II is the substantially pure (−)-enantiomer, the substantially pure (+)-enantiomer, or a racemic mixture of the (−)-enantiomer and (+)-enantiomers.

A compound comprising formula V or VI.

• wherein R8 is hydrogen, branched or straight chain C1–C8 alkyl, substituted or unsubstituted aryl, aralkyl, or CR9R10OR11, where R9 and R10 are, independently, hydrogen or alkyl, and R11 is alkyl;
• R3 is branched or straight chain C1–C4 alkyl, or substituted or unsubstituted aryl;
• X and Y are, independently, O, S, C(H)R4, or NR5, wherein R4 and R5 are, independently, hydrogen, oxygen, branched or straight chain C1–C8 alkyl, C2–C8 alkenyl, or C2–C8 alkynyl, aralkyl, or substituted or unsubstituted aryl;
• and
• R6 is hydrogen;
• C1–C8 alkyl, C2–C8 alkenyl, C2–C8 alkynyl, aralkyl, or substituted or unsubstituted aryl, or (CH2)nR7, where R7 is hydroxy, alkoxy, cyano, ester, carboxylic acid, substituted or unsubstituted amino, and n is from 1 to 4,
• with the proviso that when the compound is formula V, X is NCH3, and Y is NR5, where R5 is hydrogen, loweralkyl, arylloweralkyl, heteroarylloweralkyl, cycloalkylmethyl, or loweralkenyl methyl, R3 is not methyl or R8 is not H or loweralkyl.

A compound comprising formula X

• wherein R1 and R2 are, independently, hydrogen, branched or straight chain C1–C8 alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl;
• R3 is branched or straight chain C1–C4 alkyl or heteroalkyl or C4–C8 alkyl or heteroalkyl, or substituted or unsubstituted aryl;
• X is NR5, wherein R5 is C2-8 alkenyl, C2-8 alkynyl, or aralkyl, and
• Y is selected from C(H)R4 or NR5, wherein R4 and R5 are, independently, hydrogen, branched or straight chain C1-8 alkyl or heteroalkyl, alkenyl, or C2–C8 alkynyl, aralkyl;
• wherein the compound is the substantially pure (−)-enantiomer.

A method of inhibiting production of amyloid precursor protein in a mammalian cell, comprising contacting the mammalian cell with a compound comprising formula I

• wherein R1 and R2 are, independently, hydrogen, branched or straight chain C1–C8 alkyl, substituted or unsubstituted aryl, or aralkyl;
• R3 is branched or straight chain C1–C4 alkyl or heteroalkyl or C4–C8 alkyl or heteroakyl, or substituted or unsubstituted aryl;
• X and Y are, independently, O, S, alkyl, hydrocarbon moiety, C(H)R4, or NR5, wherein R4 and R5 are, independently, hydrogen, oxygen, branched or straight chain C1–C8 alkyl, C2–C8 alkenyl, or C2–C8 alkynyl, aralkyl, or substituted or unsubstituted aryl;
• wherein the compound is the substantially pure (+)-enantiomer,
• wherein the compound inhibits production of amyloid precursor protein in the mammalian cell.

A method of inhibiting production of amyloid precursor protein in a mammalian subject, comprising administering to the mammalian subject an effective amount of the compound comprising formula I

• wherein R1 and R2 are, independently, hydrogen, branched or straight chain C1–C8 alkyl, substituted or unsubstituted aryl, or aralkyl;
• R3 is branched or straight chain C1–C4 alkyl or heteroalkyl or C4–C8 alkyl or heteroakyl, or substituted or unsubstituted aryl;
• X and Y are, independently, O, S, alkyl, hydrocarbon moiety, C(H)R4, or NR5, wherein R4 and R5 are, independently, hydrogen, oxygen, branched or straight chain C1–C8 alkyl, C2–C8 alkenyl, or C2–C8 alkynyl, aralkyl, or substituted or unsubstituted aryl;
• wherein the compound is the substantially pure (+)-enantiomer,
• in a pharmaceutically acceptable carrier, wherein the compound inhibits production of amyloid precursor protein in the mammalian subject.

A method of treating dementia in a subject, comprising administering to the subject an effective amount of a compound comprising formula I

• wherein R1 and R2 are, independently, hydrogen, branched or straight chain C1–C8 alkyl, substituted or unsubstituted aryl, or aralkyl;
• R3 is branched or straight chain C1–C4 alkyl or heteroalkyl or C4–C8 alkyl or heteroakyl, or substituted or unsubstituted aryl;
• X and Y are, independently, O, S, alkyl, hydrocarbon moiety, C(H)R4, or NR5, wherein R4 and R5 are, independently, hydrogen, oxygen, branched or straight chain C1–C8 alkyl, C2–C8 alkenyl, or C2–C8 alkynyl, aralkyl, or substituted or unsubstituted aryl;
• wherein the compound is the substantially pure (+)-enantiomer, in a pharmaceutically acceptable carrier,
• wherein the compound treats dementia in the subject.

A method of screening a compound for the ability to inhibit production of amyloid precursor protein in a cell, comprising

• (a) contacting the cell with a compound comprising formula I
• wherein R1 and R2 are, independently, hydrogen, branched or straight chain C1–C8 alkyl, substituted or unsubstituted aryl, or aralkyl;
• R3 is branched or straight chain C1–C4 alkyl or heteroalkyl or C4–C8 alkyl or heteroakyl, or substituted or unsubstituted aryl;
• X and Y are, independently, O, S, alkyl, hydrocarbon moiety, C(H)R4, or NR5, wherein R4 and R5 are, independently, hydrogen, oxygen, branched or straight chain C1–C8 alkyl, C2–C8 alkenyl, or C2–C8 alkynyl, aralkyl, or substituted or unsubstituted aryl;
• wherein the compound is the substantially pure (+)-enantiomer;
• and
• (b) detecting a decrease in amyloid precursor protein production in the cell as compared to the amount of amyloid precursor protein produced in a control cell not contacted with the compound, whereby decreased production of amyloid precursor protein in the cell identifies the compound as having the ability to inhibit the production of amyloid precursor protein in a cell.