US2003114365A1PendingUtilityA1

Inhibitors of rotamase enzyme activity

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Assignee: GPI NIL HOLDING INCPriority: Jun 7, 1995Filed: Aug 27, 2002Published: Jun 19, 2003
Est. expiryJun 7, 2015(expired)· nominal 20-yr term from priority
Inventors:Joseph P. SteinerSolomon H. SnyderGregory S. HamiltonTed M. Dawson
A61P 43/00A61P 25/16A61P 25/02A61P 25/28A61P 25/00A61K 31/5025A61K 31/4535A61K 31/445A61K 31/444A61K 31/4545A61K 45/06A61K 31/436A61K 38/185A61K 31/4353A61K 31/453
51
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Claims

Abstract

This invention relates to the method of using neurotrophic pipecolic acid derivative compounds having an affinity for FKBP-type immunophilins as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity to stimulate or promote neuronal growth or regeneration.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A method of treating a neurological disorder in an animal, comprising: 
 administering to an animal an effective amount of a 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.    
     
     
         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 pipecolic acid derivative compound is immunosuppressive or non-immunosuppressive.  
     
     
         5 . The method of  claim 1 , wherein the pipecolic acid derivative is Way-124,666.  
     
     
         6 . The method of  claim 1 , wherein the pipecolic acid derivative is rapamycin.  
     
     
         7 . The method of  claim 1 , wherein the pipecolic acid derivative is FK506.  
     
     
         8 . The method of  claim 1 , wherein the pipecolic acid derivative is Rap-Pa.  
     
     
         9 . The method of  claim 1 , wherein the pipecolic acid derivative is SLB-506.  
     
     
         10 . The method of  claim 1 , wherein the pipecolic acid derivative is selected from the group consisting of compounds 3-84, and 86-88.  
     
     
         11 . A method of treating a neurological disorder in an animal, comprising: 
 administering to an animal an effective amount of a 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 pipecolic acid derivative inhibits said rotamase activity of the immunophilin.    
     
     
         12 . The method of  claim 11 , 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.  
     
     
         13 . The method of  claim 12 , wherein the neurological disorder is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         14 . The method of  claim 11 , wherein the pipecolic acid derivative compound is immunosuppressive or non-immunosuppressive.  
     
     
         15 . The method of  claim 11 , wherein the pipecolic acid derivative is Way-124,666.  
     
     
         16 . The method of  claim 11 , wherein the pipecolic acid derivative is rapamycin.  
     
     
         17 . The method of  claim 11 , wherein the pipecolic acid derivative is FK506.  
     
     
         18 . The method of  claim 11 , wherein the pipecolic acid derivative is Rap-Pa.  
     
     
         19 . The method of  claim 11 , wherein the pipecolic acid derivative is SLB-506.  
     
     
         20 . The method of  claim 11 , wherein the pipecolic acid derivative is selected from the group consisting of compounds 3-84, and 86-88.  
     
     
         21 . A method of stimulating growth of damaged peripheral nerves, comprising; 
 administering to damaged peripheral nerves an effective amount of a 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 pipecolic acid derivative inhibits said rotamase activity of the immunophilin.    
     
     
         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 pipecolic acid derivative is immunosuppressive or non-immunosuppressive.  
     
     
         24 . The method of  claim 21 , wherein the pipecolic acid derivative is Way-124,666  
     
     
         25 . The method of  claim 21 , wherein the pipecolic acid derivative is rapamycin.  
     
     
         26 . The method of  claim 21 , wherein the pipecolic acid derivative is FK506.  
     
     
         27 . The method of  claim 21 , wherein the pipecolic acid derivative is Rap-Pa.  
     
     
         28 . The method of  claim 21 , wherein the pipecolic acid derivative is SLB-506.  
     
     
         29 . The method of  claim 21 , wherein the pipecolic acid derivative is selected from the group consisting of compounds 3-84, and 86-88.  
     
     
         30 . A method of stimulating growth of damaged peripheral nerves, comprising: 
 administering to damaged peripheral nerves an effective amount of a 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 pipecolic acid derivative inhibits said rotamase activity of the immunophilin.    
     
     
         31 . The method of  claim 30 , 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.  
     
     
         32 . The method of  claim 30 , wherein the pipecolic acid derivative compound is immunosuppressive or non-immunosuppressive.  
     
     
         33 . The method of  claim 30 , wherein the pipecolic acid derivative is Way-124,666  
     
     
         34 . The method of  claim 30 , wherein the pipecolic acid derivative is rapamycin.  
     
     
         35 . The method of  claim 30 , wherein the pipecolic acid derivative is FK506.  
     
     
         36 . The method of  claim 30 , wherein the pipecolic acid derivative is Rap-Pa.  
     
     
         37 . The method of  claim 30 , wherein the pipecolic acid derivative is SLB-506.  
     
     
         38 . The method of  claim 30 , wherein the pipecolic acid derivative is selected from the group consisting of compounds 3-84, and 86-88.  
     
     
         39 . A method for promoting neuronal regeneration and growth in animals, comprising: 
 administering to an animal an effective amount of a 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 pipecolic acid derivative inhibits said rotamase activity of the immunophilin.    
     
     
         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 pipecolic acid derivative compound is immunosuppressive or non-immunosuppressive.  
     
     
         42 . The method of  claim 39 , wherein the pipecolic acid derivative is Way-124,666.  
     
     
         43 . The method of  claim 39 , wherein the pipecolic acid derivative is rapamycin.  
     
     
         44 . The method of  claim 39 , wherein the pipecolic acid derivative is FK506.  
     
     
         45 . The method of  claim 39 , wherein the pipecolic acid derivative is Rap-Pa.  
     
     
         46 . The method of  claim 39 , wherein the pipecolic acid derivative is SLB-506.  
     
     
         47 . The method of  claim 39 , wherein the pipecolic acid derivative is selected from the group consisting of compounds 3-84, and 86-88.  
     
     
         48 . A method for preventing neurodegeneration in an animal, comprising: 
 administering to an animal an effective amount of a pipecolic acid derivative having an affinity for FKBP-type immunophilins to prevent neurodegeneration, wherein the FKBP-type immunophilin exhibits rotamase activity and the pipecolic acid derivative inhibits said rotamase activity of the immunophilin.    
     
     
         49 . The method of  claim 48 , further comprising administering an effective amount of a neurotrophic factor to prevent neurodegeneration selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, and neurotropin-3.  
     
     
         50 . The method of  claim 48 , wherein the pipecolic acid derivative compound is immunosuppressive or non-immunosuppressive.  
     
     
         51 . The method of  claim 48 , wherein the pipecolic acid derivative is Way-124,666.  
     
     
         52 . The method of  claim 48 , wherein the pipecolic acid derivative is rapamycin.  
     
     
         53 . The method of  claim 48 , wherein the pipecolic acid derivative is FK506.  
     
     
         54 . The method of  claim 48 , wherein the pipecolic acid derivative is Rap-Pa.  
     
     
         55 . The method of  claim 48 , wherein the pipecolic acid derivative is SLB-506.  
     
     
         56 . The method of  claim 48 , wherein the pipecolic acid derivative is selected from the group consisting of compounds 3-84, and 86-88.

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