Ophthalmic uses of PPARgamma agonists and PPARgamma antagonists

Details Ophthalmic uses of PPARgamma agonists and PPARgamma antagonists Ophthalmic uses of PPARgamma agonists and PPARgamma antagonists

1999-06-28

2001-11-13

Dees, Jose′ G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S912000, C514S914000

Reexamination Certificate

active

06316465

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to the administration of drugs for the treatment of ophthalmic disorders. In one aspect, the present invention is directed to the administration of drugs which acts as ligands to modulate the activity of peroxisome proliferator-activated receptors to either treat proliferative and/or inflammatory diseases of the eye or to ameliorate or prevent degenerative diseases of the eye. In another aspect, the present invention is directed to novel compounds, and methods for making same, which can be used in the treatment of proliferative and/or inflammatory diseases of the eye and/or to ameliorate or prevent degenerative diseases of the eye.
BACKGROUND OF THE INVENTION
The peroxisome proliferator-activated receptor-&ggr; (PPAR&ggr;), a nuclear gene transcription factor, modulates the expression of genes involved in the regulation of growth and differentiation in a variety of cell types that express the receptor. PPAR&ggr; is a member of the class II family of nuclear hormone receptors which include the ligand-activated nuclear hormone transcription factors which encode the steroid, vitamin D and thyroid hormone and retinoid nuclear receptors (Mangelsdorf D J, Evans R M. Cell 1995;83:841-850). PPAR&ggr; exists as at least two isotypes, PPAR&ggr; 1 and PPAR&ggr; 2. Throughout this writing PPAR&ggr; refers to any of these isotypes or combination thereof. PPAR&ggr; 2 is expressed selectively in adipose tissue, whereas PPAR&ggr; 1 is expressed at lower levels in a variety of other rodent and human tissues (Spiegelman B M. Diabetes 1998;47:507-514).
Without limiting the present invention to any particular theory of operation, it is believed that activation of PPAR&ggr; modulates the expression of genes containing the appropriate peroxisome proliferator response element in its promoter region. PPAR&ggr; can be activated by naturally occurring nutrients such as polyunsaturated fatty acids and hormone-like arachidonic acid derivatives, and by synthetic ligands such as the antidiabetic thiazolidine-2,4-diones (Lehmann J M et al. J Biol Chem. 1995; 270:12953-12956) and N-(2-benzoylphenyl)-L-tyrosine derivatives (Henke B R et al. J Med Chem 1998; 41:5020-36). Binding of thiazolidinediones to PPAR&ggr; causes receptor activation which induces changes in the transcriptional activity of genes that downregulate and inhibit the activity of inflammatory cytokines, and promote differentiation by inhibiting proliferation. Conversely, binding of certain ligands to PPAR&ggr; can have the opposite effect, i.e. oppose differentiation (Oberfield J L et al. Proc Natl Acad Sci USA 1999; 96:6102-6). A search for endogenous PPAR&ggr; ligands identified prostaglandin J2 (PG J2) and its metabolites as PPAR&ggr; activators, with 15-deoxy-&Dgr;-12,14-PG J2 being the most potent inducer of adipogenesis. However, the thiazolidinediones had the highest affinities for PPAR&ggr;; relative affinities for various thiazolidinediones are known, for example in descending order: rosiglitazone (BRL 49653)>pioglitazone>troglitazone>15-deoxy-&Dgr;-12,14-PG J2 >15-deoxy-PG J2) (Forman B M et al. Cell 1995;83:803-12; Kliewer S A et al. Cell 1995;83:813-819).
The precise mechanism whereby ligand activation of PPAR&ggr; leads to changes in gene expression is poorly understood. Full activation of PPAR&ggr; requires its functional dimerization with the retinoid X receptor (RXR). Alterations in the conformation of the PPAR&ggr;/RXR heterodimer induced by RXR and PPAR&ggr; specific ligands may regulate gene transcription in opposing ways, depending on the nature of the ligand and its interaction with the binding domain on PPAR&ggr; (Mangelsdorf D J, Evans R M. Cell 1995;83:841-850). PPAR/RXR heterodimers can be activated independently by ligands for RXR as well as by ligands for PPAR&ggr;, or they may have a synergistic or augmented effect with dual activation (Schulman I G, et al. Mol Cell Biol. 1998; 18:3483-494). The endogenous ligand for RXR is 9-cis-retinoic acid. Nutrient retinoids such as all-trans retinoic acid are converted to 9-cis retinoic acid by a ubiquitous intracellular isomerase (Schulman I G, et al. Mol Cell Biol. 1998; 18:3483-494). The full spectrum of genes that can be regulated by PPAR&ggr; remains to be defined.
PPAR&ggr; agonists have been shown to inhibit the production of TNF-&agr; and other inflammatory cytokines by human macrophages (Jiang C-Y et al. Nature 1998; 391:82-86) and T lymphocytes (Giorgini A E et al. Horm Metab Res 1999; 31:1-4). They also inhibit proliferation and promote differentiation of breast cancer and liposarcoma cells (Mueller E et al. Mol Cell 1998; 1:465-470; Tontonoz P et al. Proc Natl Acad Sci USA 1997; 94:237-241). More recently, the natural PPAR&ggr; agonist 15-deoxy-&Dgr;-12,14-PG J2, has been shown to inhibit neovascularization and angiogenesis (Xin X et al. J Biol Chem. 1999; 274:9116-9121) in the rat cornea. Spiegelman et al., in Patent Cooperation Treaty application number PCT/US97/22879, published Jun. 18, 1998, disclose methods for inhibiting proliferation of PPAR&ggr;-responsive hyperproliferative cells by using PPAR&ggr; agonists; numerous PPAR&ggr; agonists are disclosed by Spiegelman et al., as well as methods for diagnosing PPAR&ggr;-responsive hyperproliferative cells. All documents referred to herein are incorporated by reference as if reproduced in full below. It is difficult to predict what cells and diseases are influenced by PPAR activity due to the unpredictability of PPAR expression in cells, and due to the lack of understanding of PPAR activity mechanisms. Further, PPAR is expressed in some cells while in a normal state, but not expressed or expressed to a lesser degree by the abnormal cells, or visa versa (in other words, PPAR is differentially expressed in diseased versus normal cells). For example, the present inventor has discovered that PPAR&ggr; is expressed in normal human keratinocytes but not in normal human dermal fibroblasts.
SUMMARY OF THE INVENTION
This invention is based in part on the surprising discovery that PPAR&ggr; is expressed to different degrees in the various tissues of the eye. For example, PPAR&ggr; is expressed in some but not all layers of the retina. It is confined to certain layers of the cornea, is strongly expressed in the choriocapillaris and modestly in the uveal tract. Finally, PPAR&ggr; is strongly expressed in the conjunctival epidermis and intraocular muscles but not in the ciliary muscle (Pershadsingh et al., “Ocular Diseases And Peroxisome Proliferator-Activated Receptor&ggr; (PPAR&ggr;) In Mammalian Eye,” Proc Soc Neurosci 1999, in press).
Methods of this invention include the treatment of inflammatory, proliferative, dystrophic and/or degenerative ocular diseases, such as those involving ischemia, angiogenesis, neovascularization, and/or apoptosis, by administering to a human or animal in need of treatment an effective amount of a PPAR&ggr; ligand (i.e. a PPAR&ggr; agonist or a PPAR&ggr; antagonist) to slow, reverse, or stop the disorder. The PPAR&ggr; agonist may be administered alone or in combination with a RXR ligand, a retinoid or vitamin A derivative, a flavonoid, a glucocorticoid, an androgen, an estrogen, a non-steroidal anti-inflammatory agent, a vitamin D derivative, an anti-infective agent, a protein kinase C inhibitor, a MAP kinase inhibitor, an antioxidant, an anti-apoptotic agent, a growth factor, a nutrient vitamin, an unsaturated fatty acid, or an arachidonic acid derivative.
In a preferred embodiment, suitable ligands are selected from the group consisting of a thiazolidine compound, arachidonic acid, an arachidonic acid metabolite (e.g., prostaglandin J2 or its metabolites), an hydroxamic acid derivative, a N-(2-benzoylphenyl)-L-tyrosine derivative, and a phenylacetic acid derivative. In another aspect, the present invention comprises treatment of ophthalmic disorders using matrix metalloproteinase inhibitors, some of which have PPARgamma agonist activity and antioxidant activity. A further aspect of the present invention involves novel co

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