| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 31.12.02 |
| PATENT TITLE |
Inhibitors of rotamase enzyme activity |
| PATENT 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 |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | November 5, 1999 |
| PATENT REFERENCES CITED |
Boulmedais, Chemical Abstracts, vol. 112:44174, 1989. Coleman, Chemical Abstracts, vol. 112:7219, 1989. Egbertson, Chemical Abstracts, vol. 110:57371, 1989. De Luca, Chemical Abstracts, vol. 111:23387, 19881215. Arzeno, Chemical Abstracts, vol. 110:8697, 19880316. Williams, Chemical Abstracts, vol. 109:170092, 1988. Kitamura et al., "Suppresive Effect of FK-506, a novel immunosuppressant, against MPTP-induced dopamine depletion in the striatum of young C57BL/6 mice", J. Neuroimmunology, vol. 50, pp. 221-224, Mar. 1994. Shiga et al., "Cyclosporin A protects against ischemia-reperfusion injury in the brain", Brain Res., vol. 595, pp. 145-148, 1992. Ryba et al., "Cyclosporin A Prevent Neuorlogical Deterioration of Patients with SAH-A Preliminary Report", Acta Neurochir, vol. 112, pp. 25-27, 1991. Teichner et al., "Treatment with Cyclopsorine A Promotes Axonal Regeneration in Rats Submitted to Transverse Section of the Spinal Cord", J. Hirnforsch., vol. 34, pp. 343-349, 1993. Harding, M.W. et al., "A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase," Nature Lett., 1989, 341, 758-60. Ponticelli, Claudio, "Treatment of the Nephrotic Syndrome with Cyclosporin A," J. of Autoimmunity, 1992, 5, 315-24. Tindall, Richard S.A., "Immunointervention with Cyclosporin A in Autoimmune Neurological Disorders," J. of Autoimmunity, 1992, 5, 301-13. Tugwell, Peter, "Cyclosporin in the Treatment of Rheumatoid Arthritis," J. of Autoimmunity, 1992, 5, 231-40. Fry, Lionel, "Psoriasis: Immunopathology and Long-term treatment with Cyclosporin," J. of Autoimmunity, 1992, 5, 277-83. Feutren, Gilles, "The Optimal use of Cyclosporin A in Autoimmune Diseases," J. of Autoimmunity, 1992, 5, 183-95. Munoz, Benito et al., ".alpha.-Ketoamide Phe-Pro isosterase as a new core structure for the inhibition of HIV protease," Bioorg. Med. Chem., 1994, 2(10), 1085-90. Kaczmar, et al., Makromol. Chem., 1976, 177, 1981-9. Steiner, Joseph P. et al., "High brain densities of the immunophilin FKBP colocaliized with calcineurin," Nature Lett., 1992, 584-7. Dawson, Ted M. et al., "Immunosuppresant FK506 enhances phosphorylation of nitric synthase and protects against glutamate neurotoxicity," Proc. Natl. Acad. Sci. USA, 1993, 90, 9808-12. Dragovich et al., "Structured-Based Design of Novel, Urea-Containing FKBP12 Inhibitors," J. Med. Chem., 1996, 39, 1872-1884. Gold et al., The Immunosuppresant FK506 Increases the Rate of Axonal Regeneration in Rat Sciatic Nerve, The Journal of Neuroscience, 1995, 15(11), 7509-7516. Gold et al, "The Immunosuppressant FK506 increases functional recovery and nerve regeneration following peripheral nerve injury," Restorative Neurology and Neuroscience, 1994, 6, 287-296. Lyons et al., "Immunosuppressant FK506 promotes neurite outgrowth in culture of PC12 cells and sensory ganglia," Proc. Natl. Acad. Sci. USA, 1994, 91, 3191-3195. Gold, et al, "Multiple signals underlie the anatomy-induced up-regulation of c-JUN in adult sensory neurons," Neuroscience Letters 176, 1994, 123-127. Gold et al., "Regulation of the transcription factor c-JUN by nerve growth factor in adult sensory neurons," Neuroscience Letters 154, 1993, 129-133. Sharkey et al., Chemical Abstracts, 121:221398, 1994. Kelly et al., Chemical Abstracts, 122:114965, 1994. Hearn, Chemical Abstracts, vol. 68:22217, 1967. Blaschke et al., Chemical Abstracts, 1974, 85, 78405k. Caufield, Craig E. and Musser, John H., Annual Reports in Medicinal Chemistry, Johns (ed.), Academic Press, Inc., Chapter 21, 195-204, 1989. Effenberger F. et al., "Diastereoselective addition of benzenesulfenyl chloride to 1-acryloylproline esters," Chemical Abstracts, 1989, 10, 778-9. Schreiber, Chemical Abstracts, vol. 123:275997, 950905. Rinehart, Chemical Abstracts, vol. 121:887, 940315. Takeuchi, Chemical Abstracts, vol. 122:131140, 941025. Thaisrivongs, Chemical Abstracts, vol. 117:112083, 920305. Yamada, Chemical Abstracts, vol. 117:212981, 920522. Someno, Chemical Abstracts, vol. 116:236174, 920129. Schreiber, Chemical Abstracts, vol. 116:34554, 910905. Rinehart, Chemical Abstracts, vol. 115:248086, 910418. Baader, Chemical Abstracts, vol. 116:129617, 911114. Prasit, Chemical Abstracts, vol. 115:207870, 910327. Askin, Chemical Abstracts, vol. 114:228633, 910102. Jones, Chemical Abstracts, vol. 114:81436, 900718. Takeuchi, Chemical Abstracts, vol. 115:90647, 901101. Dreyer, Chemical Abstracts, vol. 113:153045, 900124. Bieringer, Chemical Abstracts, vol. 113:226420, 900329. Askin, Chemical Abstracts, vol. 114:23615, 1990. Goulet, Chemical Abstracts, vol. 114:81347, 1990. Jones, Chemical Abstracts, vol. 112:235036, 1990. Jones, Chemical Abstracts, vol. 113:23463, 1990. Rao, Chemical Abstracts, vol. 113:191007, 1990. Waldmann, Chemical Abstracts, vol. 114:82457, 1990. Finberg, Chemical Abstracts, vol. 113:184256, 1990. Gold, Chemical Abstracts, vol. 111:195414, 890404. Gold, Chemical Abstracts, vol. 111:97735, 890228. Matsuo, Chemical Abstracts, vol. 112:158977, 890920. Goodfellow, Chemical Abstracts, vol. 111:93084, 1989. Wasserman, Chemical Abstracts, vol. 112:35516, 1989. Wasserman, Chemical Abstracts, vol. 111:57366, 1989. Askin, Chemical Abstracts, vol. 111:232396, 1989. Faelth, Chemical Abstracts, vol. 112:97901, 1989. Kocienski, Chemical Abstracts, vol. 110:212441, 1988. Tanaka, Chemical Abstracts, vol. 107:175741, 1987. Soai, Chemical Abstracts, vol. 108:38323, 1987. Munegumi, Chemical Abstracts, vol. 107:218023, 1987. Gavras, Chemical Abstracts, vol. 105:6828, 860304. Nestor, Chemical Abstracts, vol. 106:214389. Gante, Chemical Abstracts, vol. 107:97131, 860911. Soai, Chemical Abstracts, vol. 105:134309, 1986. Soai, Chemical Abstracts, vol. 107:197713, 1986. Soai, Chemical Abstracts, vol. 103:70915, 1985. Soai, Chemical Abstracts, vol. 102:78344, 1984. Harris, Chemical Abstracts, vol. 99:88574, 830222. Smith, Chemical Abstracts, vol. 100:175294, 830914. Ryan, Chemical Abstracts, vol. 100:103897, 830302. Soai, Chemical Abstracts, vol. 99:1056561, 1983. Neustadt, Chemical Abstracts, vol. 97:216730, 820505. Ryan, Chemical Abstracts, vol. 97:163506, 820324. Colombo, Chemical Abstracts, vol. 98:161133, 1982. Soai, Chemical Abstracts, vol. 98:88478, 1982. Patchett, Chemical Abstracts, vol. 95:25634, 800625. Bender, Chemical Abstracts, vol. 89:128811, 1978. Steglich, Chemical Abstracts, vol. 89:214864, 1978. Cushman, Chemical Abstracts, vol. 88:18091, 1977. Steglich, Chemical Abstracts, vol. 85:108966, 1976. Bycroft, Chemical Abstracts, vol. 84:106021, 1975. Marshall, Chemical Abstracts, vol. 83:178991, 1975. Haeusler, Chemical Abstracts, vol. 80:108833, 1974. Nakatsuta, M. et al., "Total Synthesis of FK506 and an FKBP Probe Reagent, (C.sub.8, C.sub.9 - .sup.13 C.sub.2) -FK-506," J. Am. Chem. Soc., 1990, 112 (14), 5583-90. Dawson, T.M. et al., "The immunophilins, FK506 Binding Protein and Cyclophilin, are Discretely Localized in the Brain: Relationship to Calcineurin," Neuroscience, 1994, 62(2), 569-80. Cameron, Andrew et al., "Immunophilin FK506 binding protein associated with inositol 1,4,5-triphosphate receptor modulates calcium flux," Proc. Natl. Acad. Sci. USA, 1995, 92, 1784-88. Steiner, J.P. et al., "Nonimmunosuppressive Ligands for Neuroimmunophilins Promote Nerve Extension In Vitro and In Vivo," Scoiety for Neuroscience Abstracts, 1996, 22, 297.13. Lyons, W. Ernest et al., "Neuronal Regeneration Enhances the Expression of the Immunophilin FKBP-12," The Journal of Neuroscience, 1995, 15, 2985-94. Hayward, C.M. et al., "An application of the Suarez reaction to the regiospecific synthesis of the C.sub.28 -C.sub.42 segment of rapamycin," 1993, 3989-92. Hovarth, R. et al., "An application of the Evans-Prasad 1,3-Syn diol synthesis to a stereoselective synthesis of the C.sub.10 -C.sub.27 segment of rapamycin," Tetrahedron Lett., 1993, 34(25), 3993-3996. Whitesell, J.K. et al., "Asymmetric Induction. Reduction, Nucleophilic Addition to, Ene Reactions of Chiral .alpha.-Ketoesters," J. Chem. Soc., Chem Commun., 1983, 802. Ando, Tako et al., "Formation of Crossed Phenzine from the reaction between Tetra-p-anisyl- and Tetra-p-tolyl-hydrazines in Liquid Sulphur Dioxide," Chem. Comm., S. Chem. Comm., 1975, 989. Kino, Toru et al., "FK-506, A novel immunosuppressant isolated from A Steptomyces," J. of Antibiotics, 1987, 40(9), 1249-55. Dumont, Francis J. et al., "The Immunosuppressive and Toxic Effects of FK-506 are Mechanistically Related: Pharmacology of a Novel Antagonist of FK-506 and Rapamycin," J. Exp. Med., 1992, 176, 751-760. Schreiber, Stuart L., "Chemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands," Science, 1991, 251, 282-287. Chakraborty, Chemical Abstracts, vol. 125:115111, 1999. Shu, Chemical Abstracts, vol. 124:342921, 1996. Chakraborty, Chemical Abstracts, vol. 124:290256, 1996. Slee, Chemical Abstracts, vol. 124:105570, 1995. Tatlock, Chemical Abstracts, vol. 124:86677, 1995. Teague, Chemical Abstracts, vol. 124:29474, 1995. Stocks, Chemical Abstracts, vol. 124:29735, 1995. Wang, Chemical Abstracts, vol. 123:275108, 1995. Nicolaou, Chemical Abstracts, vol. 123:285602, 1995. Armistead, Chemical Abstracts, vol. 123:217939, 1995. Luengo, Chemical Abstracts, vol. 123:187705, 1995. Furber, Chemical Abstracts, vol. 123:47577, 1995. Chakraborty, Chemical Abstracts, vol. 123:74408, 1995. Wang, Chemical Abstracts, vol. 123:74101, 1995. Smith, Chemical Abstracts, vol. 123:55541, 1995. Baumann, Chemical Abstracts, vol. 122:314327, 1995. Nelson, Chemical Abstracts, vol. 122:80964, 1994. Caffrey, Chemical Abstracts, vol. 123:82999, 1994. Birkenshaw, Chemical Abstracts, vol. 122:187213, 1994. Hauske, Chemical Abstracts, vol. 122:45705, 1994. Stocks, Chemical Abstracts, vol. 121:271263, 1994. Teague, Chemical Abstracts, vol. 121:255492, 1994. Mashkovskii, Chemical Abstracts, vol. 121:212542, 1993. Ranganathan, Chemical Abstracts, vol. 121:205990, 1994. Wang, Chemical Abstracts, vol. 121:170041, 1994. Baader, Chemical Abstracts, vol. 121:102790, 1994. Luengo, Chemical Abstracts, vol. 121:49600, 1994. Holt, Chemical Abstracts, vol. 121:224, 1994. Teague, Chemical Abstracts, vol. 121:215, 1993. Karle, Chemical Abstracts, vol. 120:324190, 1994. Skotnicki, Chemical Abstracts, vol. 120:323021, 1994. Skotnicki, Chemical Abstracts, vol. 120:323020, 1994. Holt, Chemical Abstracts, vol. 120:323019, 1993. Rao, Chemical Abstracts, vol. 120:323003, 1993. Yamashita, Chemical Abstracts, vol. 120:315168, 1994. Andrus, Chemical Abstracts, vol. 120:134101, 1993. Holt, Chemical Abstracts, vol. 120:134099, 1993. Luengo, Chemical Abstracts, vol. 120:54365, 1993. Steffan, Chemical Abstracts, vol. 120:54360, 1993. Nicolaou, Chemical Abstracts, vol. 119:270859, 1993. Hayward, Chemical Abstracts, vol. 119:249751, 1993. Pattenden, Chemical Abstracts, vol. 119:95189, 1993. Yohannes, Chemical Abstracts, vol. 119:49108, 1993. Furber, Chemical Abstracts, vol. 119:27877, 1993. Luengo, Chemical Abstracts, vol. 118:233723, 1993. Ranganathan, Chemical Abstracts, vol. 118:213513, 1993. Yohannes, Chemical Abstracts, vol. 118:147360, 1992. Hauske, Chemical Abstracts, vol. 118:22591, 1992. Cunliffe, Chemical Abstracts, vol. 117:49183, 1992. Goulet, Chemical Abstracts, vol. 116:193989, 1991. Waldmann, Chemical Abstracts, vol. 116:41997, 1991. Goulet, Chemical Abstracts, vol. 115:255882, 1991. Krit, Chemical Abstracts, vol. 115:232847, 1991. Rao, Chemical Abstracts, vol. 114:247016, 1991. Fisher, Chemical Abstracts, vol. 114:228608, 1991. Linde, Chemical Abstracts, vol. 114:206955, 1991. Long, Chemical Abstracts, vol. 118:169119, 921029. Burbaum, Chemical Abstracts, vol. 123:170197, 950613. Burbaum, Chemical Abstracts, vol. 121:109686, 940607. Armistead, Chemical Abstracts, vol. 121:170549, 940719. Armistead, Chemical Abstracts, vol. 117:131071, 920109. Holt, Chemical Abstracts, vol. 125:86501, 960229. Smith, Chemical Abstracts, vol. 125:114400, 960613. Baker, Chemical Abstracts, vol. 123:3134336 950511. Camaggi, Chemical Abstracts, vol. 124:30417, 950510. Armistead, Chemical Abstracts, vol. 122:55896, 940414. Skotnicki, Chemical Abstracts, vol. 120:54388, 931012. Luethy, Chemical Abstracts, vol. 123:313999, 930428. Frenette, Chemical Abstracts, vol. 121:35325, 931223. Krantz, Chemical Abstracts, vol. 120:245776, 930708. Ito, Chemical Abstracts, vol. 120:245780, 930720. Casini, Chemical Abstracts, vol. 120:270095, 931201. Armistead, Chemical Abstracts, vol. 119:95338, 921112. Goulet, Chemical Abstracts, vol. 118:80723, 920915. Kasahara, Chemical Abstracts, vol. 117:48221, 920304. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method of treating peripheral neuropathies caused by physical injury or disease state in a mammal comprising administering a drug to said mammal, wherein the drug forms an immunophilin-drug complex in said mammal, wherein the drug is non-immunosuppressive. 2. The method of claim 1, wherein the immunophilin is an FKBP-type immunophilin. 3. The method of claim 2, wherein the FKBP-type immunophilin is FKBP-12. 4. The method of claim 1, wherein the drug is an immunophilin ligand. 5. The method of claim 1, wherein the mammal is a human. 6. The method of claim 1, wherein the drug is administered 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. 7. A method of treating physical damage to the brain or spinal cord of a mammal comprising administering a drug to said mammal, wherein the drug forms an immunophilin-drug complex in said mammal, wherein the drug is non-immunosuppressive. 8. The method of claim 7, wherein the immunophilin is an FKBP-type immunophilin. 9. The method of claim 8, wherein the FKBP-type immunophilin is FKBP-12. 10. The method of claim 7, wherein the drug is an immunophilin ligand. 11. The method of claim 7, wherein the mammal is a human. 12. The method of claim 7, wherein the drug is administered 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. 13. A method of treating stroke associated with brain damage in a mammal comprising administering a drug to said mammal, wherein the drug forms an immunophilin-drug complex in said mammal, wherein the drug is non-immunosuppressive. 14. The method of claim 13, wherein the immunophilin is an FKBP-type immunophilin. 15. The method of claim 14, wherein the FKBP-type immunophilin is FKBP-12. 16. The method of claim 13, wherein the drug is an immunophilin ligand. 17. The method of claim 13, wherein the mammal is a human. 18. The method of claim 13, wherein the drug is administered 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. 19. A method of treating Alzheimer's Disease in a mammal comprising administering a drug to said mammal, wherein the drug forms an immunophilin-drug complex in said mammal, wherein the drug is non-immunosuppressive. 20. The method of claim 19, wherein the immunophilin is an FKBP-type immunophilin. 21. The method of claim 20, wherein the FKBP-type immunophilin is FKBP-12. 22. The method of claim 19, wherein the drug is an immunophilin ligand. 23. The method of claim 19, wherein the mammal is a human. 24. The method of claim 19, wherein the drug is administered 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. 25. A method of treating Parkinson's Disease in a mammal comprising administering a drug to said mammal, wherein the drug forms an immunophilin-drug complex in said mammal, wherein the drug is non-immunosuppressive. 26. The method of claim 25, wherein the immunophilin is an FKBP-type immunophilin. 27. The method of claim 26, wherein the FKBP-type immunophilin is FKBP-12. 28. The method of claim 25, wherein the drug is an immunophilin ligand. 29. The method of claim 25, wherein the mammal is a human. 30. The method of claim 25, wherein the drug is administered 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. 31. A method of treating amyotrophic lateral sclerosis in a mammal comprising administering a drug to said mammal, wherein the drug forms an immunophilin-drug complex in said mammal, wherein the drug is non-immunosuppressive. 32. The method of claim 31, wherein the immunophilin is an FKBP-type immunophilin. 33. The method of claim 32, wherein the FKBP-type immunophilin is FKBP-12. 34. The method of claim 31, wherein the drug is an immunophilin ligand. 35. The method of claim 31, wherein the mammal is a human. 36. The method of claim 31, wherein the drug is administered 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. 37. A method of treating a neurological disorder in a mammal comprising administering a drug to said mammal, wherein the drug forms an immunophilin-drug complex in said mammal, wherein the drug is non-immunosuppressive, wherein the neurological disorder is selected from the group consisting of trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, myasthentia gravis, muscular dystrophy, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured or prolapsed invertabrae disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, and Gullain-Barre syndrome. 38. The method of claim 37, wherein the immunophilin is an FKBP-type immunophilin. 39. The method of claim 38, wherein the FKBP-type immunophilin is FKBP-12. 40. The method of claim 37, wherein the drug is an immunophilin ligand. 41. The method of claim 37, wherein the mammal is a human. 42. The method of claim 37, wherein the drug is administered 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. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention 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. 2. Description of the Prior Art The term immunophilin refers to a number of proteins that serve as receptors for the principal immunosuppressant drugs, cyclosporin A (CsA), FK506, and rapamycin. Known classes of immunophilins are cyclophilins, and FK506 binding proteins, such as FKBP. Cyclosporin A binds to cyclophilin while FK506 and rapamycin bind to FKBP. These immunophilin-drug complexes interface with a variety of intracellular signal transduction systems, especially in the immune system and the nervous system. Immunophilins are known to have peptidyl-prolyl isomerase (PPIase) or rotamase enzyme activity. It has been determined that rotamase activity has a role in the catalyzation of the interconversion of the cis and trans isomer of immunophilin proteins. Immunophilins were originally discovered and studied in immune tissue. It was initially postulated by those skilled in the art that inhibition of the immunophilins rotamase activity leads to the inhibition of T-cell proliferation, thereby causing the immunosuppressive action exhibited by immunosuppressive drugs such as cyclosporin A, FK506, and rapamycin. Further study has shown that the inhibition of rotamase activity, in and of itself, is not sufficient for immunosuppressant activity. Schreiber et al. Science 1990, 250, 556-559. Instead immunosuppression appears to stem from the formulation of a complex of immunosuppressant drugs and immunophilins. It has been shown that the immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al., Cell 1991, 66, 807-815. In the case of FKBP-FK506 and FKBP-CsA, the drug-immunophilin complexes bind to the enzyme calcineurin, inhibiting T-cell receptor signalling leading to T-cell proliferation. Similarly, the complex of rapamycin and FKBP interacts with the RAFT1/FRAP protein and inhibits signalling from the IL-2 receptor. Immunophilins have been found to be present at high concentrations in the central nervous system. Immunophilins are enriched 10-50 times more in the central nervous system than in the immune system. Within neural tissues, immunophilins appear to influence nitric oxide synthesis, neurotransmitter release, and neuronal process extension. Nitric oxide serves several roles in the body. In the brain, nitric oxide appears to be a neurotransmitter. It is formed, from arginine, by nitric oxide synthetase which oxidizes the guanidino group of arginine forming nitric oxide and citrulline. Stimulation of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors rapidly and markedly activates nitric oxide synthetase and stimulates cGMP formation. Inhibition of nitric oxide synthetase with arginine derivatives such as nitroarginine blocks the glutamate induced increase in cGMP levels. Nitric oxide synthetase is a calcium-calmodulin requiring enzyme and N-methyl-d-aspartate receptor activation stimulates nitric oxide synthetase activity because the N-methyl-d-aspartate receptor possesses a calcium channel which is opened by glutamate stimulation, allowing calcium to rush into the cells and activate the nitric oxide synthetase. Glutamate is a physiologic neurotransmitter. However, when released in excess, glutamate elicits neurotoxicity via N-methyl-d-aspartate receptors. Treatment of cerebral cortical neuronal cultures with glutamate or N-methyl-d-aspartate kills up to 90% of neurons and these effects are blocked by N-methyl-d-aspartate antagonist drugs. This N-methyl-d-aspartate neurotoxicity is thought to be a major contributor to neuronal damage following vascular stroke. Thus, there is a massive release of glutamate following cerebral vascular occlusion and numerous N-methyl-d-aspartate antagonists block stroke damage. Phosphorylation of nitric oxide synthetase inhibits its catalytic activity. By enhancing nitric oxide synthetase phosphorylation, FK506 might functionally inhibit nitric oxide formation and thus block glutamate neurotoxicity. Indeed, low concentrations of FK506 and cyclosporin A both block N-methyl-d-aspartate neurotoxicity in cortical cultures. The mediating role of FKBP is evident, as rapamycin reverses the therapeutic effect of FK506. Presumably FK506, already marketed as an immunosuppressant, could be clinically employed in stroke patients. FK506 also augments the phosphorylation of growth-associated protein-43 (GAP43). GAP43 is involved in neuronal process extension and its phosphorylation appears to augment this activity. Accordingly, the effects of FK506 rapamycin and cyclosporin in neuronal process extension have been examined using PC12 cells. PC12 cells are a continuous line of neuronal-like cells which extend neurites when stimulated by nerve growth factor (NGF). Surprisingly, it has been found that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate neurite out growth in PC12 cells and sensory nervous, namely dorsal root ganglion cells (DRGs). Lyons et al. proc. Natl. Acad. Sci. USA, 1994, 91, 3191-3195. In whole animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve injury and results in functional recovery in animals with sciatic nerve lesions. More particularly, it has been found that drugs with a high affinity for FKBP are potent rotamase inhibitors and exhibit excellent neurotrophic effects. Snyder et al., "Immunophilins and the Nervous System", Nature Medicine, Volume 1, No. 1, Jan. 1995, 32-37. These findings suggest the use of immunosuppressants in treating various peripheral neuropathies and enhancing neuronal regrowth in the central nervous system (CNS). Studies have demonstrated that neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) may occur due to the loss, or decreased availability, of a neurotrophic substance specific for a particular population of neurons affected in the disorder. Several neurotrophic factors effecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer's disease results from a decrease or loss of nerve growth factor (NGF). It has thus been proposed to treat Alzeheimer's patients with exogenous nerve growth factor or other neurotrophic proteins such as brain derived growth factor, glial derived growth factor, ciliary neurotrophic factor, and neurotropin-3 to increase the survival of degenerating neuronal populations. Clinical application of these proteins in various neurological disease states is hampered by difficulties in the delivery and bioavailability of large proteins to nervous system targets. By contrast, immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity. However, when administered chronically, immunosuppressants exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis (Kopp et al., 1991, J. Am. Soc. Nephrol. 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina such as non-localized headaches (De Groen et al., 1987, N. Engl. J. Med. 317:861); and vascular hypertension with complications resulting therefrom (Kahan et al., 1989 N. Engl. J. Med. 321: 1725). The present invention provides non-immunosuppressive as well as immunosuppressive p-ipecolic acid derivative cmpounds containing small molecule FKBP rotamase inhibitors which are extremely potent in augmenting neurite outgrowth, and for promoting neuronal growth, and regeneration in various neuropathological situations where neuronal repair can be facilitated including peripheral nerve damage by physical injury or disease state such as diabetes, physical damage to the central nervous system (spinal cord and brain), brain damage associated with stroke, and for the treatment of neurological disorders relating to neurodegeneration, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. SUMMARY OF THE INVENTION 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. A preferred embodiment of this invention is 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. Another preferred embodiment of this invention is 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. Another preferred embodiment of this invention is 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. Another preferred embodiment of this invention is 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. Another preferred embodiment of this invention is 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. Yet another preferred embodiment of this invention is a method for preventing neurodegeneration in an animal, comprising: administering to an animal an effective amount of a pipecolic acid erivative 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. |
| PATENT PHOTOCOPY | Available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |