Analogs of glycyl-prolyl-glutamate
Embodiments of this invention include novel analogs of Glycyl-Prolyl-Glutamate (GPE) and compositions containing such analogs of GPE. Of these, certain analogs have modified proline residues. Other embodiments of this invention include uses of analogs of GPE to protect neural cells from degeneration and/or death in response to injury or disease. Disorders treatable with compounds and compositions of this invention include hypoxia/ischemia, toxic injury, and chronic neurodegenerative disorders including Parkinson's disease.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein:
the bond between X 1 and X 2 is either saturated or unsaturated;
X 1 is S;
X 2 is selected from the group consisting of CH 2 , CH 2 CH 2 and in the case where the bond between X 1 and X 2 is unsaturated, CH;
R 1 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, substituted alkyl, substituted alkenyl, substituted aryl or substituted arylalkyl;
R 2 is CH 3 or COOH;
R 3 is selected from the group consisting of H, alkyl or NR 3 R 3′ taken together is pyrrolidino or piperidino;
R 4 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, substituted alkyl, substituted alkenyl, substituted aryl or substituted arylalkyl;
R 5 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, substituted alkyl, substituted alkenyl, substituted aryl or substituted arylalkyl; and
n is an integer from 0 to 2.
2. The compound of claim 1 where X 1 is S; X 2 is CH 2 ; R 1 is H; R 2 is COOH; R 3 is H; R 4 is H; R 5 is H; and n is 0 (Glycyl-L-4-thiaprolyl-L-glutamic acid trifluoroacetate).
3. The compound of claim 1 where X 1 is S; X 2 is CH 2 ; R 1 is H; R 2 is COOH; R 3 is H; R 4 is CH 3 ; R 5 is H; and n is 0 (Glycyl-L-thia-5,5-dimethylprolyl-L-glutamic acid (“G-thiadiMePE”)).
4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 4 , further comprising a binder.
6. The pharmaceutical composition of claim 4 , further comprising a capsule.
7. A method of treating an animal to protect neural cells from death or degeneration as a result of an injury or disease wherein the injury or disease is a result of one or more conditions selected from the group consisting of chronic or acute encephalomyelitis, encephalitis, optic neuritis, transverse myelitis, meningitis, panencephalitis, Devic's disease, progressive multifocal leukoencephalopathy, central pontine myelinolysis, neuromyelitis optica, neuroblastoma, head injury, traumatic brain injury, stroke, ischemic injury, hypoxic injury, reperfusion injury, epilepsy, cardiac artery bypass graft surgery, toxin damage, radiation damage and asphyxia comprising administering to said animal an effective amount of one or more compounds of claim 1 .
8. The method of claim 7 wherein the animal is human.
9. The method of claim 7 wherein the injury or disease is characterised by apoptotic neuronal death.
10. The method of claim 7 wherein the injury or disease is characterised by necrotic neuronal death.
11. The method of claim 7 , wherein the injury or disease is characterized by neuronal cell degeneration.
12. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable excipient.
13. The pharmaceutical composition of claim 12 , further comprising a binder.
14. The pharmaceutical composition of claim 12 , further comprising a capsule.