Helical peptidomimetics
Helical peptidomimetic compounds as inhibitors of beta-amyloid production are provided. These inhibitors preferably inhibit intramembrane proteases, notably aspartyl secretases involved in the enzymatic cleavage of amyloid precursor protein (APP) to yield amyloid-β peptide. Methods are provided for making a medicament containing the compounds and for administering the compounds to treat β-amyloid-associated diseases, notably Alzheimer's disease.
1. A composition consisting of a peptide having the following sequence: Boc-D-Val-Gly-Aib-D-Val-D-Val-D-BPA-Aib-D-Thr(OBz)-D-Val-Aib-OMe (SEQ ID NO:11),
wherein Boc is t-butyloxycarbonyl;
wherein OBz is O-benzyl ester;
wherein OMe is O-methyl ester;
wherein Aib is aminoisobutyric acid; and
wherein BPA is 4-benzoylphenylalanine.
2. A composition comprising a pharmaceutically acceptable salt of the composition of claim 1 .
3. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier.
4. The composition of claim 1 , further comprising a carrier to promote delivery of the compound of claim 1 to a brain.
5. A method of treating a subject having or at risk of having a β-amyloid-associated disease, comprising:
administering to a subject having or at risk of having a β-amyloid-associated disease a therapeutically effective amount of a composition according to claim 1 to treat the β-amyloid-associated disease.
6. The method of claim 5 , wherein the β-amyloid-associated disease is a neurodegenerative disease.
7. The method of claim 5 , wherein the β-amyloid-associated disease is Alzheimer's disease.
8. The method of claim 5 , wherein the compound is administered to the subject in combination with an effective amount of a second agent useful in the treatment of β-amyloid-associated disease.
9. The method of claim 8 , wherein the second agent is an acetylcholinesterase inhibitor.
10. The method of claim 5 , wherein the compound is orally administered.
11. A pharmaceutical composition comprising the composition of claim 1 , in a therapeutically effective amount to treat a β-amyloid associated disease.
12. The pharmaceutical composition of claim 11 , wherein the β-amyloid associated disease is Alzheimer's disease.
13. The composition of claim 2 , further comprising a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising the composition of claim 2 , in a therapeutically effective amount to treat a β-amyloid associated disease.
15. The pharmaceutical composition of claim 14 , wherein the β-amyloid associated disease is Alzheimer's disease.