Non-peptidic cyclophilin binding compounds and their use

Details Non-peptidic cyclophilin binding compounds and their use Non-peptidic cyclophilin binding compounds and their use

2001-05-21

2003-07-15

Padmanabhan, Sreeni (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C514S478000, C514S479000, C514S482000, C514S491000, C514S589000, C514S590000, C514S596000

Reexamination Certificate

active

06593362

ABSTRACT:

This invention relates to pharmaceutical compositions and methods of using non-peptidic cyclophilin-binding compounds in medical conditions involving breakdown of mitochondrial energy metabolism induced by calcium overload, in treating alopecia and promoting hair growth, in treating infections with filarial and helmintic parasites, and in treating and preventing infections with the human immunodeficiency virus.
The cyclic undecapeptide cyclosporin A (CyA), as well as two other drugs, FK-506 and rapamycin, are well-known in the art as potent T-cell specific immunosuppressants, and are effective against graft rejection after organ transplantation. In vivo and in vitro, these compounds bind to two distinct classes of proteins commonly known as immunophilins. Cyclophilins (CyP), which bind cyclosporin A, and FK506-binding proteins (FKBP), which bind FK-506 and rapamycin, are both subclasses of this group of proteins termed immunophilins. Immunophilins were first identified as proteins that bind to the immunosuppressive drugs cyclosporin A, FK506, and rapamycin. CyPs and FKBPs can also be separated based on their differing structures.
The effects of the cyclosporin A:cyclophilin interaction have been well documented. Cyclosporin A binds with a dissociation constant in the range of 10
−8
mol/L, a value representing a relatively high degree of attraction (Handschumacher et al.,
Science
226:544 (1984)). While the present invention is not bound by any particular theory, it appears the complex formed between CyP and cyclosporin A exerts the effects on the organism and cells, which leads to immunosuppression. The complex interacts with the cellular enzyme calcineurin, a calmodulin-dependent phosphatase, and the interaction prevents T cell activation by blocking RNA transcription of the T cell growth factor interleukin 2 (IL-2). (Palacios,
J. Immunol.
128:337 (1982)). Without IL-2 to cause T cell proliferation, specific T cell populations cannot mount a strong immune response, resulting in immunosuppression.
A number of types of mammalian cyclophilins have been identified and cloned, cyclophilins A, B, C, D, and cyclophilin-40 (Snyder and Sabatini,
Nat. Med.
1:32-37 (1995); Friedman et al.,
Proc. Natl. Acad. Sci.,
90:6815-6819 (1993)). Cyclophilin A is a 19 kD protein, which is abundantly expressed in a wide variety of cells. Like the other cyclophilins, cyclophilin A binds the immunosuppressive agent cyclosporin A and possesses peptidyl-prolyl cis-trans isomerase (PPIase) and protein folding or “chaperone” activities. PPIase activity catalyzes the conversion of proline residues in a protein from the cis to the trans conformation (Fischer, et al.,
Biomed. Biochem. Acta
43:1101-1112 (1984)). Cyclophilin B possesses an N-terminal signal sequence that directs translocation into the endoplasmic reticulum of the cell. The 23 kD cyclophilin C is found in the cytosol of the cell. Cyclophilin D, at 18 kD, appears to target its actions in the mitochondria. And cyclophilin-40 is a component of the inactivated form of a glucocorticoid receptor.
Since immunophilins, including the cyclophilin group of proteins, were discovered because of their interaction with known immunosuppressive drugs, drug discovery efforts initially focused on improving the immunosuppressant potency, and optimizing the pharmacological profile, of cyclosporin A and its peptidic analogues for immunosuppressant uses. Later, other biological effects of immunosuppressant cyclophilin-binding drugs were discovered. It has been reported that, in murine models which mimic human premature hair follicle regression or human chemotherapy-induced hair loss, topical application of CsA induces and maintains hair growth, and topical or systemic administration of CsA protects from hair loss induced by cancer chemotherapeutic agents (see, e.g., Maurer, et al.
Am. J. Pathol.
150(4): 1433-41 (1997); Paus, et al.,
Am. J. Pathol.
144, 719-34 (1994)). One form of hair loss, alopecia areata, is known to be associated with autoimmune biological processes; hence, topically administered immunomodulatory compounds are expected to be efficacious in treating this particular form of hair loss. However, there is evidence that initiation of hair growth by CsA is unrelated to immunosuppression (Iwabuchi, et al.,
J. Dermatol. Sci.
9, 64-69 (1995)).
FK506 has also been shown to stimulate hair growth in a dose-dependent manner when administered topically (Yamamoto, et al.,
J. Invest. Dermatol.
102 (1994) 160-164; Jiang, et al.,
J. Invest. Dermatol.,
104 (1995) 523-525).
The use of cyclosporin A and related compounds for hair revitalization has been disclosed in U.S. Pat. No. 5,342,625 (Hauer et al.), U.S. Pat. No. 5,284,826 (Eberle), U.S. Pat. No. 4,996,193 (Hewitt et al.). These patents relate to compounds and compositions useful for treating immune-related disorders and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth. The known utility of cyclosporin A in promoting hair growth has also been cited in earlier work by the present inventors, see, e.g., U.S. Pat. No. 6,172,087 B1 (Steiner and Hamilton), U.S. Pat. No. 6,177,455 B1 (Steiner and Hamilton), U.S. Pat. No. 6,187,784 B1 (Steiner and Hamilton).
Another biological activity of the cyclophilin-binding compounds cyclosporin and its peptidic analogues relates to their protective effects on proapoptotic cells. The mitochondrion is increasingly being recognized as an important mediator of cell death in hypoxia, ischemia, and chemical toxicity. Disruption of the mitochondrial transmembrane potential is observed before other features of apoptosis (e.g. generation of reactive oxygen species or internucleosomal DNA fragmentation (“laddering”)) become detectable. This applies to many different models of apoptosis induction, such as, for example, NGF-deprivation of cultured sympathetic neurons, dexamethasone-induced lymphocyte apoptosis, programmed lymphocyte death, activation-induced programmed cell death of T cell hybridomas, and tumor necrosis factor-induced death of lymphoma cells. [Marchetti, P., et al., J. Exp. Med. 184, 1996, 1155-1160]. Breakdown of mitochondrial transmembrane potential in proapoptotic cells has been attributed to the formation of an unspecific high conductance channel—the mitochondrial permeability transition pore—which leads to an increased permeability of the inner mitochondrial membrane to small molecular weight solutes. The ensuing release of intramitochondrial ions, influx of solutes, uncoupling of oxidative phosphorylation, and loss of metabolic intermediates accompanies large amplitude mitochondrial swelling and a depletion of cellular energy stores [see, e.g., Lemasters, J. J. et al., Mol. Cell. Biochem. 174 (1997) 159-165]. Importantly, CsA and non-immunosuppressive peptidic CsA analogues have been described to potently block pore conductance and inhibit the onset of the mitochondrial permeability transition [Broekemeier, K. M., et al., J. Biol. Chem. 264 (1989) 7826-7830; Zamzami, M., et al., FEBS Lett. 384 (1996) 53-7]. The mitochondrial permeability transition pore forms under calcium overload conditions such as occur in ischemia/reperfusion injury, and it has been found that administration of CsA and/or non-immunosuppressive peptidic CsA analogues, by blocking the permeability transition pore, leads to significant protection in experimental models of cerebral stroke [Matsumoto, S., et al., J. Cereb. Blood Flow Metab. 19 (1999) 736-41], cardiac ischemia [Griffiths, E. J. and Halestrap, A. P., J. Mol. Cell Cardiol. 25 (1993) 1461-1469], and hepatic ischemia/reperfusion injury [Leducq, N., et al., Biochem. J. 336 (1998) 501-6 ].
CsA and its non-immunosuppressive peptidic analogues have also been found to potently inhibit the growth of pathogenic protozoan parasites, such as
Cryptosporidium parvum, Plasmodium falciparum, Plasmodium vivax, Schistosoma spec
., and
Toxoplasma gondii
[Perkins, et al.,
Antimicrob. Agents Chemother.
42: 843-848 (1998)]

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