Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-17
2002-07-09
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252020, C514S252030, C514S252040, C514S252050, C514S252060, C514S218000, C514S406000, C514S407000, C540S553000, C544S238000, C548S356100, C548S364100, C548S364100, C548S364100, C548S364400, C548S364100, C548S364100, C548S364700
Reexamination Certificate
active
06417189
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to N-substituted cyclic aza compounds, pharmaceutical compositions comprising such compounds, and methods of their use for effecting neuronal activities.
DESCRIPTION OF RELATED ART
Neuroimmunophilins
The peptidyl-prolyl isomerases (“PPIases”) are a family of ubiquitous enzymes which catalyze the interconversion of cis and trans amide bond rotamers adjacent to proline residues in peptide substrates. See, for example, Galat, A.,
Eur. J. Biochem
. (1993) 216:689-707 and Kay, J. E.,
Biochem. J
. (1996) 314:361-385. The PPIases have been referred to as “immunophilins” because of their interaction with certain immunosuppressant drugs. Schreiber, S. L.,
Science
(1991) 251:283-287; Rosen, M. K. and Schreiber, S. L.,
Angew. Chem. Intl. Ed. Engi
. (1992) 31:384-400.
The PPIase, cyclophilin A, was found to be the intracellular protein target for the potent immunosuppressant drug cyclosporin A. Subsequently, the structurally unrelated macrolide immunosuppressant FK506 was discovered to bind to a different PPIase enzyme which was named FK506-binding protein, or FKBP. Rapamycin, another macrolide drug which is a structural analogue of FK506, also interacts with FKBP.
All three of these drugs bind to their respective immunophilins and inhibit the respective PPIase activities. However, inhibition of immunophilin enzymatic activity is not the cause of the observed immunosuppressive effects. Binding of the drugs to the immunophilins results in the formation of “activated complexes”, which interact with downstream proteins to inhibit proliferation of T-lymphocytes. Schreiber, supra; Rosen, et al., supra. In the case of FK506, binding to FKBP results in a drug-protein complex which is a potent inhibitor of the calcium-calmodulin-dependent protein phosphatase, calcineurin. Bierer, B. E., Mattila, P. S., Standaert, R. F., Herzenberg, L. A., Burakoff, S. J., Crabtree, G., Schreiber, S. L.,
Proc. Natl. Acad. Sci. USA
(1990) 87:9231-9235; Liu, J., Farmer, J. D., Lane, W. S., Friedman, J., Weissman, I., Schreiber, S. L.;
Cell
(1991) 66:807-815.
Neither FK506 or FKBP alone appreciably inhibits calcineurin's activity. Inhibiting calcineurin blocks the signaling pathway by which the activated T-cell receptor causes transcription of the gene for interleukin-2, inhibiting the immune response. Despite the structural dissimilarity between FK506 and cyclosporin A (and cyclophilin and FKBP), the cyclosporin A-cyclophilin complex also inhibits calcineurin, and thus cyclosporn A and FK506 have the same mechanism of action.
On the other hand, while rapamycin and FK506 have similar structures and bind to the same immunophilin (FKBP), rapamycin's mechanism of action is different from that of FK506. The complex of FKBP12 with rapamycin interacts with a protein called FPAP, or RAFT, and in so doing blocks the signal pathway leading from the IL-2 receptor on the surface of T-cells to promotion of entry into the cell cycle in the nucleus. Sabatini, D. M., Erdjument-Bromage, H., Lui, M.; Tempst, P., Snyder, S. H.,
Cell
(1994) 78:35-43; Brown, E. J., Albers, M. W., Shin, T. B., Ichikawa, K., Keith, C. T., Lane, W. S., Schreiber, S. L.
Nature
(1994) 369:756-758; Brown, E. J., Beal, P. A., Keith, C. T., Chen, J., Shin, T. B., Schreiber, S. L., Nature (1995) 377:441-446.
Thus, all three drugs produce the same effect—suppression of T-cell proliferation—but do so by inhibiting distinct signal transduction pathways. The introduction of cyclosporin(“CsA”) marked a breakthrough in organ transplantation, and the drug became a major pharmaceutical product. The subsequent discovery of rapamycin (“Rapamycin”) and FK506 further fueled interest in the cellular basis of the actions of these drugs. The discovery of the interaction of the immunophilins with CsA, FK506 and Rapamycin led to research on the mechanistic basis of immunophilin-mediated immunosuppression.
Immunophilins and the Nervous System
Because the initial interest in the immunophilins was largely driven by their role in the mechanism of action of the immunosuppressant drugs, most of the original studies of these proteins and their actions focused on the tissues of the immune system. In 1992, it was reported that levels of FKBP12 in the brain were 30 to 50 times higher than in the immune tissues. Steiner, J. P., Dawson, T. M., Fotuhi, M., Glatt, C. E., Snowman, A. M., Cohen, N., Snyder, S. H.,
Nature
(1992) 358:584-587. This finding suggested a role for the immunophilins in the functioning of the nervous system. Both FKBP and cyclophilin were widely distributed in the brain and were found almost exclusively within neurons. The distribution of the immunophilins in the brain closely resembled that of calcineurin, suggesting a potential neurological link. Steiner, J. P., Dawson, T. M., Fotuhi, M., Glatt, C. E., Snowman, A. M., Cohen, N., Snyder, S. H.,
Nature
(1992) 358:584-587; Dawson, T. M., Steiner, J. P., Lyons, W. E., Fotuhi, M., Blue, M., Snyder, S. H.,
Neuroscience
(1994) 62: 569-580.
Subsequent work demonstrated that the phosphorylation levels of several known calcineurin substrates were altered in the presence of FK506. Steiner, J. P., Dawson, T. M., Fotuhi, M., Glatt, C. E., Snowman, A. M., Cohen, N., Snyder, S. H.,
Nature
(1992) 358:584-587. One of the proteins affected by FK506 treatment, GAP-43, mediates neuronal process elongation. Lyons, W.E., Steiner, J. P., Snyder, S. H., Dawson, T. M.,
J. Neurosci
. (1995) 15:2985-2994. This research revealed that FKBP12 and GAP-43 were upregulated in damaged facial or sciatic nerves in rats. Also, FKBP12 was found in very high levels in the growth cones of neonatal neurons. FK506 was tested to determine whether or not it might have an effect on nerve growth or regeneration. In cell culture experiments with PC12 cells or sensory neurons from dorsal root ganglia, FK506 promoted process (neurite) extension with subnanomolar potency. Lyons, W. E., George, E. B., Dawson, T. M., Steiner, J. P., Snyder, S. H.,
Proc. Nati. Acad. Sci. USA
(1994) 91:3191-3195. Gold et al. demonstrated that FK506 functioned as a neurotrophic agent in vivo. In rats with crushed sciatic nerves, FK506 accelerated nerve regeneration and functional recovery. Gold, B.G., Storm-Dickerson, T., Austin, D. R. ,
Restorative Neurol. Neurosci
., (1994) 6:287; Gold, B. G., Katoh, K., Storm-Dickerson, T. J,
Neurosci
. (1995) 15:7509-7516. See, also, Snyder, S. H., Sabatini, D. M.,
Nature Medicine
(1995) 1:32-37 (regeneration of lesioned facial nerves in rats augmented by FK506).
Besides FK506, rapamycin and cyclosporin also produced potent neurotrophic effects in vitro in PC12 cells and chick sensory neurons. Steiner, J. P., Connolly, M. A., Valentine, H. L., Hamilton, G. S., Dawson, T. M., Hester, L., Snyder, S. H.,
Nature Medicine
(1997) 3:421-428. As noted above, the mechanism for immunosuppression by rapamycin is different than that of FK506 or cyclosporin. The observation that rapamycin exerted neurotrophic effects similar to FK506 and cyclosporin suggested that the nerve regenerative effects of the compounds are mediated by a different mechanism than that by which they suppress T-cell proliferation.
Analogues of FK506, rapamycin, and cyclosporin which bind to their respective immunophilins, but are devoid of immunosuppressive activity, are known in the art. Thus, the FK506 analogue L-685,818 binds to FKBP but does not interact with calcineurin, and is therefore nonimmunosuppressive. Dumont, F. J., Staruch, M. J., Koprak, S. L.,
J. Exp. Med
. (1992) 176:751-760.
Similarly, 6-methyl-alanyl cyclosporin A (6-[Me]-ala-CsA) binds to cyclophilin but likewise lacks the ability to inhibit calcineurin. The rapamycin analogue WAY-124,466 binds FKBP but does not interact with RAFT, and is likewise nonimmunosuppressive. Ocain, T. D., Longhi, D., Steffan, R. J., Caccese, R. G., Sehgal, S. N.,
Biochem. Biophys. Res. Commun
. (1993) 192:1340-1346; Sigal, N. H., Dumont, F., Durette, P., Siekierka, J. J., Peterson, L., Rich, D.,
J. Exp. Med
. (1991) 173:619-628. These
Hamilton Gregory S.
Huang Wei
Wu Yong-Qian
GPI NIL Holdings Inc.
Lyon & Lyon LLP
Raymond Richard L.
Truong Tamthom N.
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