Patent EA-001379-B1 (EA)
Title: Method of treating a neurological disorder in a mammal, method of stimulating and promoting growth of damaged peripheral nerves, method, for promoting neuronal regeneration and growth and method for preventing neurodegeneration in a mammal
Inventor: STEINER JSEPH P
IPC: A61P25/28
Filed: 1996-06-05
Abstract: 1. A method of treating a neurological disorder in an animal, comprising administering to an animal an effective amount of a non-immunosuppressive pipecolic acid derivative having an affinity for FKBP-type immunophilins to stimulate growth of damaged peripheral nerves or to promote neuronal regeneration, wherein the FKBP-type immunophilin exhibits rotamase activity and the pipecolic acid derivative inhibits said rotamase activity of the immunophilin and the pipecolic acid derivative having the formula   where R can be oxygen or nitrogen, X and Y can be any substituents, wherein X and Y can be bonded to each other forming a ring. 2. The method of claim 1, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies cause by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders relating to neurodegeneration. 3. The method of claim 2, wherein the neurological disorder is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis. 4. The method of claim 1, wherein the non-immunosuppressive pipecolic acid derivative is Way-124,666. 5. The method of claim 1, wherein the non-immunosuppressive pipecolic acid derivative is SLB-506. 6. The method of claim 1, wherein the non-immunosuppressive pipecolic acid derivative is selected from the group consisting of compounds 3-84, 86-88 and 90-111. 7. The method of claim 1, wherein the method provides at least 75% regeneration of axon number and at least 35% recovery of myelination. 8. The method of claim 1, wherein the method provides at least 75% regeneration of axon number and at least 50% recovery of myelination. 9. The method of claim 1, wherein rotamase inhibition is achieved using no greater than a 1800 nM concentration of the compound. 10. The method of claim 1, wherein rotamase inhibition is achieved using no greater than a 210 nM concentration of the compound. 11. The method of claim 1, wherein rotamase inhibition is achieved using no greater than a 103 nM concentration of the compound. 12. The method of claim 1, wherein neurotrophic ED50 is achieved using no greater than a 200 nM concentration of the compound. 13. The method of claim 1, wherein neurotrophic ED50 is achieved using no greater than a 35 nM concentration of the compound. 14. The method of claim 1, wherein neurotrophic ED50 is achieved using no greater than a 1 nM concentration of the compound. 15. A method of treating a neurological disorder in an animal, comprising administering to an animal an effective amount of a non-immunosuppressive pipecolic acid derivative having an affinity for FKBP-type immunophilins in combination with an effective amount of a neurotrophic factor selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, and neurotropin-3, to stimulate growth of damaged peripheral nerves or to promote neuronal regeneration, wherein the FKBP-type immunophilin exhibits rotamase activity and the non-immunosuppressive pipecolic acid derivative inhibits said rotamase activity of the immunophilin and the pipecolic acid derivative having the formula   where R can be oxygen or nitrogen, X and Y can be any substituents, wherein X and Y can be bonded to each other forming a ring. 16. The method of claim 15, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies cause by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders relating to neurodegeneration. 17. The method of claim 15, wherein the neurological disorder is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis. 18. The method of claim 15, wherein the non-immunosuppressive pipecolic acid derivative is Way-124,666. 19. The method of claim 15, wherein the non-immunosuppressive pipecolic acid derivative is SLB-506. 20. The method of claim 19, wherein the non-immunosuppressive pipecolic acid derivative is selected from the group consisting of compounds 3-84, 86-88 and 90-111. 21. A method of stimulating growth of damaged peripheral nerves, comprising administering to damaged peripheral nerves an effective amount of a non-immunosuppressive pipecolic acid derivative compound having an affinity for FKBP-type immunophilins to stimulate or promote growth of the damaged peripheral nerves, wherein the FKBP-type immunophilins exhibit rotamase activity and the non-immunosuppressive pipecolic acid derivative inhibits said rotamase activity of the immunophilin and the pipecolic acid derivative having the formula   where R can be oxygen or nitrogen, X and Y can be any substituents, wherein X and Y can be bonded to each other forming a ring. 22. The method of claim 21, further comprising administering a neurotrophic factor to stimulate or promote growth of the damaged peripheral nerves selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, and neurotropin-3. 23. The method of claim 21, wherein the non-immunosuppressive pipecolic acid derivative is Way-124,666. 24. The method of claim 21, wherein the non-immunosuppressive pipecolic acid derivative is SLB-506. 25. The method of claim 21, wherein the non-immunosuppressive pipecolic acid derivative is selected from the group consisting of compounds 3-84, 86-88 and 90-111. 26. The method of claim 21, wherein the method provides at least 75% regeneration of axon number and at least 35% recovery of myelination. 27. The method of claim 21, wherein the method provides at least 75% regeneration of axon number and at least 50% recovery of myelination. 28. The method of claim 21, wherein rotamase inhibition is achieved using no greater than a 1800 nM concentration of the compound. 29. The method of claim 21, wherein rotamase inhibition is achieved using no greater than a 210 nM concentration of the compound. 30. The method of claim 21, wherein rotamase inhibition is achieved using no greater than a 103 nM concentration of the compound. 31. The method of claim 21, wherein neurotrophic ED50 is achieved using no greater than a 200 nM concentration of the compound. 32. The method of claim 21, wherein neurotrophic ED50 is achieved using no greater than a 35 nM concentration of the compound. 33. The method of claim 21, wherein neurotrophic ED50 is achieved using no greater than a 1 nM concentration of the compound. 34. A method of stimulating growth of damaged peripheral nerves, comprising administering to damaged peripheral nerves an effective amount of a non-immunosuppressive pipecolic acid derivative compound having an affinity for FKBP-type immunophilins to stimulate growth of damaged peripheral nerves, wherein the FKBP-type immunophilin exhibit rotamase activity and the non-immunosuppressive pipecolic acid derivative inhibits said rotamase activity of the immunophilin and the pipecolic acid derivative having the formula   where R can be oxygen or nitrogen, X and Y can be any substituents, wherein X and Y can be bonded to each other forming a ring. 35. The method of claim 34, further comprising administering an effective amount of a neurotrophic factor selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, and neurotropin-3 to stimulate the growth of damaged peripheral nerves. 36. The method of claim 34, wherein the non-immunosuppressive pipecolic acid derivative is Way-124,666. 37. The method of claim 34, wherein the non-immunosuppressive pipecolic acid derivative is SLB-506. 38. The method of claim 34, wherein the non-immunosuppressive pipecolic acid derivative is selected from the group consisting of compounds 3-84, 86-88 and 90-111. 39. A method for promoting neuronal regeneration and growth in animals, comprising administering to an animal an effective amount of a non-immunosuppressive pipecolic acid derivative compound having an affinity for FKBP-type immunophilins to promote neuronal regeneration, wherein the FKBP-type immunophilins exhibit rotamase activity and the non-immunosuppressive pipecolic acid derivative inhibits said rotamase activity of the immunophilin and the pipecolic acid derivative having the formula   where R can be oxygen or nitrogen, X and Y can be any substituents, wherein X and Y can be bonded to each other forming a ring. 40. The method of claim 39, further comprising administering an effective amount of a neurotrophic factor to promote neuronal regeneration selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, and neurotropin-3. 41. The method of claim 39, wherein the non-immunosuppressive pipecolic acid derivative is Way-124,666. 42. The method of claim 39, wherein the non-immunosuppressive pipecolic acid derivative is SLB-506. 43. The method of claim 39, wherein the non-immunosuppressive pipecolic acid derivative is selected from the group consisting of compounds 3-84, 86-88 and 90-111. 44. The method of claim 39, wherein the method provides at least 75% regeneration of axon number and at least 35% recovery of myelination. 45. The method of claim 39, wherein the method provides at least 75% regeneration of axon number and at least 50% recovery of myelination. 46. The method of claim 39, wherein rotamase inhibition is achieved using no greater than a 1800 nM concentration of the compound. 47. The method of claim 39, wherein rotamase inhibition is achieved using no greater than a 210 nM concentration of the compound. 48. The method of claim 39, wherein rotamase inhibition is achieved using no greater than a 103 nM concentration of the