GPE analogs and peptidominetics
View Patent ↗This invention relates to analogs and peptidomimetics of glycyl-L-prolyl-L-glutamic acid (GPE). In particular, this invention relates to GPE analogs and peptidomimetics that are anti-apoptotic and anti-necrotic, to methods of making them, to pharmaceutical compositions containing them, and to their use.
1. A compound of Formula 1:
wherein: m=0; n=1; X=NH 2 ; Y=CO 2 H; Z=CO 2 H; R 1 =R 3 =R 4 =H; and R 2 =CH 3 , or a salt thereof.
2. A pharmaceutical composition comprising the compound of claim 1 , further comprising a pharmaceutically acceptable excipient.
3. The composition of claim 2 , for oral administration, comprising a dosage form having an amount of said compound having a lower limit of about 1 mg/Kg and an upper limit of about 100 mg/Kg.
4. The composition of claim 3 , wherein said dosage form further comprises a binder.
5. The composition of claim 2 , wherein said compound is present in a an amount having a lower limit of about 0.0001 percent by weight; and an upper limit of about 10% by weight.
6. The composition of claim 2 , wherein said compound is associated with a semi-permeable polymer matrix.
7. The composition of claim 6 , wherein said semi-permeable polymer matrix is selected from the group consisting of polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methylacrylate), ethylene vinyl acetate, liposomes and poly-D-(−)-3-hydroxybutyric acid.
8. A capsule for oral administration comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
9. A tablet containing the compound of claim 1 and a binder.
10. The composition of claim 2 , wherein said pharmaceutically acceptable excipient is isotonic saline.
11. A method for treating neural degeneration, caused by hypoxia-ischemia or toxic injury comprising administering a pharmaceutical composition comprising a pharmacologically effective amount of the compound of claim 1 to a subject in need of such treatment.
12. The method of claim 11 , wherein said effective amount is in the range having a lower limit of about 0.001 mg/Kg and an upper limit of about 1 gm/Kg.
13. The method of claim 11 , wherein said composition is administered by an oral, topical, systemic, parenteral, subcutaneous, intravenous, intraspinal, intracisternal, intraventricular, implantation, infusion, or aerosol route.
14. The method of claim 11 , wherein said hypoxia-ischemia or toxic injury is to the central nervous system.
15. The method of claim 11 , wherein said hypoxia-ischemia or toxic injury is associated with degeneration of neurons of the central nervous system.
16. The method of claim 15 , wherein said neurons are one or more of striatal, cerebellar or cortical neurons.