WO2008138350A1 - Prévention d'une fibrose intra-oculaire - Google Patents

Prévention d'une fibrose intra-oculaire Download PDF

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WO2008138350A1
WO2008138350A1 PCT/DK2008/050107 DK2008050107W WO2008138350A1 WO 2008138350 A1 WO2008138350 A1 WO 2008138350A1 DK 2008050107 W DK2008050107 W DK 2008050107W WO 2008138350 A1 WO2008138350 A1 WO 2008138350A1
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Lars Michael Larsen
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Sygehuset Glostrup
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to compounds capable of inhibiting intraocular fibrosis and their use for treatment and prevention of conditions that threaten visual function with specific emphasis on the prevention and treatment of subretinal fibrosis in eyes with subretinal choroidal neovascularization secondary to age-related macular degeneration, myopia, choroidal rupture, choroiditis, angioid streaks, and similar conditions, and the prevention and treatment of preretinal fibrosis secondary to neovascular proliferative retinopathy, retinal vein occlusion, sickle cell disease, uveitis, retinopathy of prematurity, proliferative vitreoretinopathy, traction retinal detachment, rubeosis iridis, neovascular glaucoma, and other diseases of the retinal and/or optic nerve characterized by the development of scar tissue within or adjacent to nervous tissue or elsewhere.
  • Scar tissue formation in the eye may arise in relation to choroidal neovascularization in age-related macular degeneration, scar tissue being most prominent after involution of the actively exudating and bleeding vascular growth phase, whence scar tissue may occupy the entire subretinal space behind the foveal photoreceptors, thus depriving the photoreceptors of the neurosensory retina of contact with a functioning retinal pigment epithelium.
  • Prevention or inhibition of subretinal fibrosis can be achieved by photocoagulation, verteporfin-photodynamic therapy, or intravitreal pharmacologic inhibition of vascular endothelial growth factor.
  • subretinal fibrosis treatments have not been shown, however, to be fully capable of preventing subretinal fibrosis in subretinal neovascularization.
  • Other causes of subretinal fibrosis include degenerative myopia, choroidal rupture, outer retinal scarring and Bruch's membrane scarring following choroiditis, angioid streaks, or other causes of outer retinal injury
  • Scar tissue formation in the eye may occur in relation to disease that leads to the formation of preretinal and/or optic nerve head neovascularization, including for instance proliferative diabetic retinopathy, retinal vein occlusion, sickle cell disease, and uveitis. Scar tissue formation typically peaks later than new vessel formation, often concurrent with the involution of the new vessels and in the same location.
  • a vascular endothelial growth factor inhibitor (ranibizumab or bevacizumab) can be followed by prompt regression of preretinal new vessels.
  • a vascular endothelial growth factor inhibitor (ranibizumab or bevacizumab)
  • Scar tissue formation in the eye has also been seen following rhegmatogenous retinal detachment, a condition known as proliferative vitreoretinopathy.
  • fibrosis occurs without prior new vessel formation, fibrocytes believed to be formed as the result of transformation of ectopic retinal pigment epithelial cells in the vitreous and on the inner surface of the retina, or in the subretinal space.
  • vitrectomy with preretinal membrane excision is the only generally accepted treatment for traction retinal detachment.
  • Scar tissue formation in the eye may occur as a result of retinopathy of prematurity, apparently as a sequel to the formation of new vessels emanating from a demarcation line between vascularized and nonvascularized tissue in the immature peripheral retina.
  • Current methods of treatment including cryoablation and photoablation of the avascular retina, are insufficient to fully prevent visual loss secondary to traction retinal detachment caused by contracting preretinal fibrosis membranes.
  • vitrectomy with preretinal membrane excision is the only accepted treatment for traction retinal detachment. Invasion of the subretinal space by choroidal new vessels is a major cause of visual loss in age-related macular degeneration (AMD).
  • Neovascular AMD benefits from treatment that specifically inhibits vascular endothelial growth factor (VEGF), but the treatment only leads to normalization of visual acuity in very few patients and approximately 30% experience considerable visual loss despite treatment
  • VEGF vascular endothelial growth factor
  • Neovascularization and inflammation in the anterior segment of the eye may complicate anterior segment disease as well as retinal disease, choroidal disease, or optic nerve disease. Severe cases can be accompanied by the formation of fibrous membranes on the iris, on the ciliary body, and in the anterior chamber angle.
  • fibrosis is an integral part of the process that leads to visual loss in said diseases, because fibrosis is difficult or impossible to remove, and because damage caused by fibrosis can be difficult or impossible to repair there is a strong rationale for applying therapeutic remedies that can eliminate or reduce the fibrotic component of the said diseases.
  • transforming growth factor beta TG F- ⁇
  • TGF- ⁇ activity can be inhibited by blocking the angiotensin ll-receptor (A2R) (Habashi et al. Science 2006, 312: 1 17-121 ).
  • A2R angiotensin ll-receptor
  • Angiotensin Il inhibition by captopril or other angiotensin-converting enzyme inhibitors has effects that are comparable with A2R-inhibition, suggesting that this is a class effect of medications that block angiotensin Il receptor signalling.
  • the effect appears to be mediated through inhibition of Smad3.
  • Investigations of human retinal pigment epithelium (RPE) cell cultures support that inhibition of Smad3 can attenuate fibrotic transformation of RPE cells (Saika S et al. Laboratory Investigation 2005;85:838-850).
  • A2R-signaling Several inhibitors of A2R-signaling have been shown to be clinically effective in reducing morbidity and mortality in arterial hypertension and to have an attractive safety profile that matches the preventive scope and relatively large numbers- needed-to-treat of such treatment. Despite widespread use, no significant adverse ocular effects have been reported for such medications. Consequently, inhibition of A2R signalling is likely to have an attractive safety profile as a method of inhibiting intraocular fibrosis in a range of debilitating eye diseases.
  • angiotensin converting enzyme (ACE) inhibitor treatment and A2R inhibitor treatment can inhibit the development and progression of manifestations of mild-to-moderate stages diabetic retinopathy (Larsen et al. Graefe's Arch Clin Exp Ophthalmol 228:505 509, 1990). It has been suggested that inhibition of fibrosis may contribute to the effect in later stages of diabetic retinopathy (Wilkinson-Berka JL. International Journal of Biochemistry & Cell Biology 38 (2006) 752-765). The literature suggests that in prefibrotic stages of diabetic retinopathy the effect is mediated by the antihypertensive effects of these agents. Indeed, blood pressure reduction using a beta blocker has been found to have a comparable effect to that of ACE inhibitor treatment (UK Prospective Diabetes Study Group, BMJ, 1998;317:713-20.
  • the ACE inhibitor lisinopril and the A2R inhibitor losartan have been shown to inhibit retinal neovascularization (Moravski. Hypertension 2000;36:1099-1 104), a stage that may be followed by fibrosis. Retinal fibrosis is not, however, an inevitable sequel or accompaniment of retinal neovascularization.
  • the angiotensin Il receptor blocker candesartan is currently being evaluated as a means of preventing diabetic retinopathy and inhibiting diabetic retinopathy progression in the DIRECT trial (Sj ⁇ lie and Chaturvedi, Journal of Human Hypertension 2002; 16, S42-S46).
  • RAAS Renin-Angiotensin-Aldosterone System
  • the Renin-Angiotensin-Aldosterone System (RAAS) is activated in response to low arterial blood pressure, decreased serum sodium concentration, decreased blood volume, and sympathetic stimulation.
  • the kidneys release renin, which cleaves the liver-produced angiotensinogen into Angiotensin I.
  • Angiotensin I is then converted to angiotensin Il by angiotensin-converting-enzyme (ACE) in the pulmonary circulation.
  • ACE angiotensin-converting-enzyme
  • the system in general serves to maintain blood pressure.
  • the target for a medicament of the of the present invention is renin, also known as angiotensinogenase - a circulating enzyme released mainly by juxtaglomerular cells in the juxtaglomerular apparatus (JGA) of the kidney in response to low blood volume or low NaCI concentration and which is mediated through the rapid release of prostaglandins.
  • renin has hormone-like actions, it cleaves a protein precursor in the circulation rather than working on a cellular target. Thus it is not truly a hormone.
  • Sympathetic activation of membrane ⁇ 1 - and ⁇ 1 -adrenergic receptors on JGA cells also cause renin release, probably by altering tubular sodium content or macula densa function.
  • the normal concentration in human plasma is 1 .0-2.5 mg/ml.
  • renin precursor consists of 406 amino acids with a pre and a pro segment carrying 20 and 46 amino acids respectively.
  • Mature renin contains 340 amino acids and has a mass of 37 kD.
  • Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced in the liver, to yield angiotensin I, which is further converted into angiotensin Il by ACE, the angiotensin-converting enzyme.
  • ACE angiotensin-converting enzyme
  • This is a membrane- bound enzyme present on the surface of the vascular endothelium of blood vessels throughout the body.
  • the lung is the primary organ responsible for angiotensin Il conversion, due to the large endothelial surface area of the many capillaries used in gas exchange. Angiotensin Il then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, all leading to increased blood pressure.
  • Renin is secreted from juxtaglomerular cells, which are activated via signalling (the release of prostaglandins) from the macula densa, which respond to the rate of fluid flow through the distal tubule, by decreased renal perfusion pressure (through stretch receptors in the vascular wall), and by nervous stimulation, mainly through beta-1 receptor activation.
  • a drop in the rate of flow past the macula densa implies a drop in renal filtration pressure. Renin's primary function is therefore to eventually cause an increase in blood pressure, leading to restoration of perfusion pressure and filtration in the kidneys.
  • Renin can bind to ATP6AP2, which results in a four-fold increase in the conversion of angiotensinogen to angiotensin I over that shown by soluble renin. In addition, renin binding results in phosphorylation of serine and tyrosine residues of ATP6AP2.
  • An over-active renin-angiotension-aldosteron system leads to vasoconstriction and retention of sodium and water. These effects lead to hypertension. Renin inhibitors known to date include Tekturna (aliskiren).
  • the medicament of the present invention is an angiotensin receptor - a class of G protein-coupled receptors for which angiotensins act as ligands. They are important in the renin-angiotensin-aldosterone system where they are responsible for the signal transduction of the main effector hormone.
  • angiotensin receptors The classification of the angiotensin receptors is based on their pharmacological properties (i.e. selective agonists and antagonists, ligand-binding affinities), transduction mechanisms, and structural features.
  • pharmacological properties i.e. selective agonists and antagonists, ligand-binding affinities
  • transduction mechanisms i.e. selective agonists and antagonists, ligand-binding affinities
  • structural features i.e. selective agonists and antagonists, ligand-binding affinities
  • AT1 and AT2 Two major types of mammalian receptor have been cloned and are designated by the abbreviations AT1 and AT2.
  • angiotensin Il Most of the known actions of angiotensin Il are mediated through the AT1 receptor and serve to maintain blood pressure and glomerular filtration rate in the face of extracellular volume depletion.
  • angiotensin Il has been viewed as a blood- borne hormone produced in the circulation, it is also formed in many tissues such as the brain, kidney, heart, and blood vessels, where angiotensin Il functions as a paracrine and autocrine hormone.
  • the AT1 and AT2 receptors are members of the seven transmembrane-domain (7TM), G protein-coupled receptor superfamily.
  • AT1 receptors are their selective affinity for biphenylimidazoles (typified by losartan) and their insensitivity to tetrahydroimidazopyridines such as PD123177.
  • the AT2 receptor has low affinity for losartan and high affinity for PD123177 and a peptide derivative, CGP421 12.
  • AT1 A and AT1 B originate from two closely related, but distinct, encoding genes that are located on chromosomes 17 and 2, respectively.
  • AT1 A and AT1 B receptors differ in 19 amino acids (aa), mainly in the C-terminal region. Both rodent types have identical binding and functional properties. They are, however, differentially regulated.
  • the AT1 receptor has a molecular mass of 41 kDa and contains three N- glycosylation sites, eight phosphorylation sites, and six cysteine residues.
  • the three- dimensional structure of the AT1 receptor is maintained by two disulphide bridges.
  • High-affinity binding of angiotensin Il is determined by amino acids located on or near the extracellular surface of the membrane-bound receptor, as well as by sequences in the transmembrane domains. These are probably in close proximity in the native receptor and held together by the disulphide bridges.
  • the structural integrity of the AT1 receptor can be disrupted by reducing agents. Binding of non- peptide antagonists such as losartan occurs at distinct sites involving TMIII-VI. Agonist binding to the AT1 receptor is reduced by GTP, suggesting the existence of heterogeneous states of receptor affinity due to association with G proteins.
  • the AT1 receptor is mainly expressed in vascular smooth muscle, liver, kidney, heart, lung, adrenal cortex, pituitary and brain.
  • the process of agonist binding leads to the attachment of Gq/G1 1 and/or Gi/Go proteins to the third cytoplasmic loop and C-terminal of the receptor, and to the stimulation of several intracellular signalling pathways.
  • the complex signalling events induced by angiotensin Il occur multiphasically within seconds, minutes or hours, and involve the selective activation of multiple pathways over time.
  • the signal transduction mechanisms of the AT1 receptor depend on at least five different effectors: phospholipase (PL) C (formation of lns(1 ,4,5)P3 and DAG); voltage-dependent Ca2+ channels; PLD (cleavage of phosphatidylcholine); PLA2 (formation of prostaglandins and prostanoids); and adenylate cyclase (decrease in cAMP production).
  • PL phospholipase
  • PLD cleavage of phosphatidylcholine
  • PLA2 formation of prostaglandins and prostanoids
  • adenylate cyclase decrease in cAMP production.
  • angiotensin II like many growth factors, stimulates the phosphorylation of several tyrosine- containing proteins such as mitogen-activated protein (MAP) kinase as well as the JAK-STAT pathway[16,17].
  • MAP mitogen-activated protein
  • the gene coding for the AT2 receptor is located on chromosome X. Unlike the AT1 receptor, no additional types or splice variants of the AT2 receptor have been reported in either man or rodents. Similar in structure to the AT1 receptor, the AT2 receptor has a molecular mass of 41 kDa. The receptor contains five N-glycosylation sites, five phosphorylation sites, and 14 cysteine residues. The arrangements of the cysteine residues in the AT2 receptor render it resistant to reducing agents. There is also a lack of effect of GTP analogues upon ligand-binding to AT2 sites.
  • AT2 receptor is developmentally regulated: it is highly expressed in various foetal tissues and at a lower density in adult adrenal medulla, brain, and reproductive tissues. It appears to be re-expressed or up-regulated after vascular injury, myocardial infarction, cardiac failure or wound healing, possibly reflecting re- activation of a foetal genetic programme. Preclinical in vitro and in vivo studies indicated that the AT2 receptor counterbalances the effect of the AT1 receptor.
  • the signal transduction mechanism of the AT2 receptor is still poorly understood. Although the 'DRY sequence Asp141 -Arg142-Tyr143 and the amino acid Asp90 involved in G protein-activation of PLC by AT1 and other such receptors are retained, agonist stimulation of the AT2 receptor does not induce an increase in lnsP3 and DAG formation. A Gi ⁇ 2-3 protein susceptible to pertussis toxin has been reported to participate in the signal transduction mechanism of the AT2 receptor. Depending on the tissues, activation of the AT2 receptor appears to stimulate intracellular mechanisms involving Tyr and Ser/Thr phosphatases such as MKP-1 , SHP-1 and PP2A, leading to the inactivation of the AT-1 receptor- and growth factor-activated kinases.
  • the AT2 receptor when inducing cell differentiation, can also stimulate MAP kinases Erk1/Erk2. As a consequence, there is an inactivation of MAP kinase, antiproliferation, promotion of apoptosis, repolarization trough opening of delayed-rectifier K+ channels and calcium and voltage activated potassium channel, closing of T -type Ca 2+ channels and vasodilation.
  • the phosphatase activity is controlled by a cellular redox mechanism involving bradykinin, nitric oxide and cGMP formation. Through its phosphatase activity, the AT2 receptor regulates the NFKB pathway and interferes with the inflammatory process.
  • the AT2 receptor does not require receptor phosphorylation or heterotrimeric G ⁇ y protein to be active.
  • Angiotensin IV (Ang IV) or Angiotensin 3-8 as it is sometimes referred to binds selectively, reversibly, saturably and with high affinity (Kd 1 nM) to a binding site termed AT4, which has very low affinity for Ang Il and for the AT1 and AT2 receptor antagonists.
  • This receptor is widely distributed in brain and peripheral organs such as heart, vessels, adrenals, kidney, colon and prostate.
  • Stable synthetic analogues of Ang IV such as Norleucine 1 -Ang IV and divalinal-Ang IV act as AT4 receptor agonist and antagonist ligands, respectively. It appears that LVV-haemorphin is an endogenous ligand for the AT4 receptor.
  • the AT4 receptor has been recently identified as the membrane-associated oxytocinase/insulin regulated aminopeptidase (OTase/IRAP), OTase being the human homologue of IRAP. There is 95% identity between the purified AT4 receptor and IRAP. Ang IV and LVV- haemorphin compete for the binding of 125l-Nle1 -Ang IV in IRAP-transfected HEK293 cells with IC50 values in the nanomolar range. Covalent binding studies on AT4 binding sites have consistently revealed the presence of a 165 kDa peptide similar to that of IRAP.
  • OTase/IRAP is a type Il integral membrane protein, homologous to aminopeptidases A, N, and other Zn 2+ -dependent aminopeptidases. It has a short intracellular domain, a single transmembrane-spanning domain and a large extracellular domain containing the catalytic site. It colocalized with Glut-4 vesicles. Ang IV inhibits the activity of OTase/IRAP and thereby reduces the processing of other bioactive peptides such as oxytocin, metenkephalin, dynorphin, neuromedin.
  • bioactive peptides such as oxytocin, metenkephalin, dynorphin, neuromedin.
  • AT4 receptor-signaling pathway Knowledge of the AT4 receptor-signaling pathway is far from complete, but it does not involve classic second messengers such as cAMP and lnsP3. In addition, the AT4 receptor does not seem to be coupled to a G protein. Whether the AT4 binding domain functions as a receptor as well as an enzyme regulatory site has yet to be determined. It is likely that Ang IV has a physiological role in various functions such as cognition, cardiovascular and renal metabolism, and also in pathological conditions such as diabetes and hypertension. Ang IV could be promoting the release of vasodilators such as nitric oxide, causing collagen accumulation in hypertrophied heart, controlling sodium transport in the kidney.
  • vasodilators such as nitric oxide
  • the target for medication is the angiotensin converting enzyme (ACE), also known as peptidyl dipeptidase A carboxycathepsin, kininase Il (kinin-kallikrein system), CD 143 and ACE1 catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and is involved in the inactivation of bradykinin, a potent vasodilator.
  • ACE angiotensin converting enzyme
  • Inhibitors of Angiotensin-Converting Enzyme are a group of medicaments that previously mainly have been used in treatment of hypertension and congestive heart failure, in most cases as the drugs of first choice.
  • ACE inhibitors lower arteriolar resistance and increase venous capacitance; increase cardiac output and cardiac index, stroke work and volume, lower renovascular resistance, and lead to increased natriuresis (excretion of sodium in the urine).
  • ACE inhibitors have also been shown to be effective for indications other than hypertension even in patients with normal blood pressure.
  • ACE inhibitors can be divided into three groups based on their molecular structure. The first group is Sulfhydryl-containing ACE inhibitors such as Captopril (Capoten®), the first ACE inhibitor. The second and largest group comprise dicarboxylate-containing ACE inhibitors such as Enalapril
  • the target for a medicament of the present invention is the aldosterone receptor, sometimes referred to as the mineralocorticoid receptor (or MR, MLR, MCR), or nuclear receptor subfamily 3, group C, member 2, (NR3C2) and is a receptor with high affinity for mineralocorticoids. It belongs to the steroid hormone receptor family where the ligand diffuses into cells, interacts with the receptor and results in a signal transduction affecting specific gene expression in the nucleus.
  • the mineralocorticoid receptor or MR, MLR, MCR
  • NRC2 nuclear receptor subfamily 3, group C, member 2,
  • the gene for the NR3C2 (located on chromosome 4q31 .1 -31.2) encodes for the 107 kDa MR protein.
  • MR is expressed in many tissues, such as the kidney, colon, heart, central nervous system (hippocampus), brown adipose tissue, and sweat glands.
  • the receptor is activated by mineralocorticoids such as aldosterone and deoxycorticosterone as well as glucocorticoids, like Cortisol and cortison. It also responds to some progestins.
  • mineralocorticoids such as aldosterone and deoxycorticosterone as well as glucocorticoids, like Cortisol and cortison. It also responds to some progestins.
  • Spironolactone and eplerenone are known MR antagonists.
  • the present invention describes the use of inhibitors of A2R signalling as a prophylactic and therapeutic remedy against intraocular disease associated with the development of intraocular fibrosis. Accordingly, the present invention relates to the use of a medicament capable of interfering with a component of the Renin-Angiotensin-Aldosteron signalling system for the treatment or prevention, or treatment and prevention of scar tissue generated in the eye of an individual in relation to treatment of angiogenesis or in relation to the treatment of inflammation or in relation to the treatment of vascular leakage.
  • An important embodiment of the present invention relates to the use of at least one compound capable of inhibiting A2R signalling in an individual, in the manufacture of a medicament for prevention or treatment of a disease that may lead to intraocular fibrosis, or associated symptoms and complications thereof, in a mammal, in particular a human being.
  • the invention relates, in a main aspect, to a method for prevention and/or treatment of intraocular fibrosis, or associated symptoms and complications thereof, in a mammal, comprising administering to said mammal a pharmaceutically efficient amount of at least one compound capable of inhibiting A2R signalling in the eye, by local or systemic administration.
  • the present invention has the potential to eradicate an important direct cause of visual loss in people of the working ages in industrialized countries and substantially reduce the sufferings of patients with various types of eye disease.
  • the present invention is directed to a medicament for prevention or treatment of an ocular disorder related to intraocular fibrosis comprising at least one compound capable of inhibiting A2R signalling in an individual, as an active ingredient.
  • compositions suitable for local administration as an eyedrop instilled into the conjunctival sac, as a fluid injection into or adjacent to the outside of the eye, as a solid implant into the eye, or as a systemically administered pharmaceutical composition administered orally, or parenterally, comprising a pharmaceutically effective amount of at least one compound capable of inhibiting A2R signalling.
  • Intraocular fibrosis may include, but is not restricted to, locations such a the subretinal space, intraretinal fibrosis, epiretinal fibrosis and fibrosis on the posterior aspect of the vitreous body
  • the invention relates to the use of compounds capable of inhibiting A2R signalling and thereby reducing or eliminating the development of fibrosis or the maturation of immature connective tissue for prevention and/or treatment of diseases and conditions that reduce or threaten to reduce visual function.
  • Administering in the context of "administering to a mammal” refers to delivering the therapeutic agents in question to an organism. Administration can be systemic, topical, or local administration as described herein, or the implantation of a slow-release device to the subject.
  • Fibrosis The term “fibrosis” is used here to denote the biological response that leads to the deposition of extracellular material with properties similar to those of connective tissue.
  • Inhibition of fibrosis means stopping, eliminating, or slowing down any or more processes that lead to formation of extracellular material with properties similar to or identical to that of connective tissue.
  • a pharmaceutically efficient amount means the amount of a pharmaceutical agent or multidrug therapeutic which elicits a positive response on at least one symptom of a disease state, or which acts prophylactically to reduce the likelihood of at least one pathological symptoms or consequences of a disease state, i.e. to inhibit the onset or progression of the disease.
  • Prevention refer to prevention of the occurrence of a disease in a subject that may be predisposed to a disease but has not yet been diagnosed as having it. It will also be appreciated that “prevention” and “preventing” can also involve a reduction in the likelihood of adverse consequences of a pathological state. Thus, “prevention” and “preventing” as used herein can also refer to prophylaxis.
  • Renin-anqiotensin-aldosteron system The term renin-angiotensin-aldosterone system (RAAS) as used herein plays an important role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. As the name implies, there are three important components to this system: 1 ) renin, 2) angiotensin, and 3) aldosterone. Renin, which is primarily released by the kidneys, stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex.
  • renin-angiotensin-aldosterone system renin-angiotensin-aldosterone system
  • scar tissue as used herein is defined as any space-filling component of a tissue or an organ made up of cells and/or formed extracellular components that are not natural elements of the tissue or organ under conditions of health.
  • scar tissue in the eye consists of fibroblasts and/or fibrocytes or transformed retinal pigment epithelial cells which are found in abnormal locations, abnormal amounts or accompanied by abnormal extracellular tissue, replacing or displacing healthy tissue such as photoreceptors and pigment epithelial cells after the healthy cells have died or causing healthy cells to died and become dysfunctional.
  • healthy tissue such as photoreceptors and pigment epithelial cells after the healthy cells have died or causing healthy cells to died and become dysfunctional.
  • scar tissue in the eye is known as intraocular fibrosis.
  • therapeutic agent means any agent useful for therapy.
  • treatment refers to any treatment of a disease in a mammal, particularly a human being, and generally include inhibiting the disease, i.e. arresting its development, or relieving the disease, i.e. causing regression of the disease. Treating also refers to providing a beneficial alteration in one or more of the symptoms of a disease state or reducing or eliminating the disease state itself. It will be appreciated that a beneficial alteration can include transitory or permanent reduction or elimination of the symptom.
  • vascular leakage as used herein is defined as any condition where intravenous fluorescein angiographic study or intravenous indicyanine angiographic study or any other study, by intravenous or intraarterial injection or oral ingestion of a tracer substance or by use of intrinsic markers of the integrity of the vascular wall, such as assessment of plasma protein and/or plasma lipid in the retina or choroid, in soluble or precipitatetd form, of the perfusion and patency of the retinal or choroidal vessels shows that abnormal leakage occurs, has occurred or is likely to occur in the future.
  • Retinal vascular leakage can be counterbalanced by processes that remove excess extracellular fluid or it can give rise to edema (swelling) of the retina, detachment of the retina by fluid, and/or precipitation within or adjacent to the retina of plasma proteins and/or lipid.
  • vascular leakage is understood to mean not only leakage through the inner blood-retinal barrier but also leakage through the outer blood- retinal barrier, i.e. the retinal pigment epithelium.
  • generation of scar tissue has occurred subsequent to treatment of angiogenesis.
  • the development of scar tissue has occurred during treatment of angiogenesis.
  • the treatment of angiogenesis was performed using compounds interfering with vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • the target of said medicament capable of interfering with a component of the Renin-Angiotensin- Aldosteron signalling system for the treatment or prevention is Angiotensin 2 Receptor (A2R) of subtype AT1 (SEQ ID NO.1 ), AT2 (SEQ ID NO.2).
  • A2R Angiotensin 2 Receptor
  • the target of said medicament capable of interfering with a component of the Renin-Angiotensin-Aldosteron signalling system for the treatment or prevention is Angiotensin Converting Enzyme (SEQ ID NO. 3).
  • the target of said medicament capable of interfering with a component of the Renin-Angiotensin-Aldosteron signalling system is Renin (SEQ ID NO.4).
  • the target of said medicament capable of interfering with a component of the Renin-Angiotensin-Aldosteron signalling system is an aldosteron receptor (SEQ ID NO.5).
  • the target of said medicament capable of interfering with a component of the Renin-Angiotensin-Aldosteron signalling system for the treatment or prevention is a combination of one or more of renin, the angiotensin receptors AT1 and AT2 and/or angiotensin converting enzyme and/or the aldosterone receptor(s).
  • the medicament capable of interfering with the Renin-Angiotensin-Aldosteron signalling system contains a compound selected among captopril, lisinopril, quinapril, benazepril, enalapril, perindopril, fosinopril, trandolapril, ramipril, cilazapril, spirapril, delapril, moexipril, temocapril, zofenopril and imidapril.
  • the medicament capable of interfering with the Renin-Angiotensin-Aldosteron signalling system contains a compound selected among losartan, irbesartan, valsartan, telmisartan, candesartan, olmesartan, eprosartan, tasosartan.
  • the medicament capable of interfering with the Renin-Angiotensin-Aldosteron signalling system contains a compound selected among spironolactone and eplerenone.
  • said medicament capable of interfering with the Renin-Angiotensin-Aldosteron signalling system is administered orally or parenterally.
  • said medicament capable of interfering with the Renin-Angiotensin-Aldosteron signalling system is administered intraocularly such as in the form of an intravitreal, intracameral, subretinal, or subscleral (epichoroidal) injection or as a subtenonal or other type of juxtascleral injection.
  • said medicament capable of interfering with the Renin-Angiotensin-Aldosteron signalling system is administered in dosages of from about 0.1 ⁇ g/kg of total body weight to about 10 mg/kg of total body weight, such as 0.1 ⁇ g/kg of total body weight, for example 0.2 ⁇ g/kg of total body weight, such as 0.3 ⁇ g/kg of total body weight, for example 0.4 ⁇ g/kg of total body weight, such as 0.5 ⁇ g/kg of total body weight, for example 0.6 ⁇ g/kg of total body weight, such as 0.7 ⁇ g/kg of total body weight, for example 0.8 ⁇ g/kg of total body weight, such as 0.9 ⁇ g/kg of total body weight, for example 1 .0 ⁇ g/kg of total body weight, such as 1 .1 ⁇ g/kg of total body weight, for example 1 .2 ⁇ g/kg of total body weight, such as 1 .3 ⁇ g/kg of total body weight,
  • said components of said medicaments are administered as a slow-release formulation wherein said slow- release formulation is a device wherein the medicament is held confined by mechanical or physico-chemical effects.
  • the said medicament is confined by polymer binding, co-polymerization, embedding of the active compound in polymers, gels, solids, adsorption and other types of non-covalent or covalent binding conferring inactivity and/or sequestration in the bound form together with mechanisms of gradual release that increase or otherwise alter the pharmacokinetic profile of the active agent.
  • the pharmaceutically active compound of said medicament capable of interfering with a component of the Renin-Angiotensin- Aldosteron signalling system is administered in the form of a pharmaceutically acceptable addition of salt or hydrate of said compound such as selected from bromide, chloride, fluoride, hydride, iodide, nitride, oxide, phosphide, sulfide, peroxide, borate, bromate, hypobromite, carbonate, hydrogen carbonate, bicarbonate, chlorate, perchlorate, chlorite, hypochlorite, chromate, iodate, nitrate, nitrite, phosphate, hydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, thiosulfate, hydrogen sulfate, bisulfate, sulfite, hydrogen sulfite, bisulfite, acetate, formate, oxalate, hydrogen o
  • the pharmaceutically active compound of said medicament capable of interfering with a component of the Renin-Angiotensin- Aldosteron signalling system is covalently bound to a delivery-enhancing transporter by chemical or recombinant methods.
  • said medicament capable of interfering with a component of said Renin-Angiotensin-Aldosteron signalling system is a pro-drug of the general formula X-acetonide, wherein X is an A2R-inhibitor.
  • said medicament capable of interfering with a component of said Renin-Angiotensin-Aldosteron signalling system is administered by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation wherein said injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration wherein said injection is performed singularly or plurally.
  • said plurally performed administration of said medicament capable of interfering with a component of said Renin-Angiotensin- Aldosteron signalling system wherein said plurally performed administration of said medicament occurs at intervals of 30 minutes to 24 hours or at intervals of 1 to 6 hours.
  • the duration of the treatment with said medicament capable of interfering with a component of said Renin-Angiotensin- Aldosteron signalling system is from 6 to 72 hours.
  • the duration of the treatment with said medicament capable of interfering with a component of said Renin-Angiotensin- Aldosteron signalling system is from 1 to 14 days.
  • the duration of the treatment with said medicament capable of interfering with a component of said Renin-Angiotensin- Aldosteron signalling system is from 4 to 10 days.
  • the duration of the treatment with said medicament capable of interfering with a component of said Renin-Angiotensin- Aldosteron signalling system is from 10 to 30 days.
  • the duration of the treatment with said medicament capable of interfering with a component of said Renin-Angiotensin- Aldosteron signalling system is from 15 to 25 days.
  • the duration of the treatment with said medicament capable of interfering with a component of said Renin-Angiotensin- Aldosteron signalling system is from 1 to 365 days, such as 2 days, for example 3 days, such as 4 days, for example 5 days, such as 6 days, for example 7 days, such as 8 days, for example 9 days, such as 10 days, for example 1 1 days, such as 12 days, for example 13 days, such as 14 days, for example 15 days, such as 16 days, for example 17 days, such as 18 days, for example 19 days, such as 20 days, for example 21 days, such as 22 days, for example 23 days, such as 24 days, for example 25 days, such as 26 days, for example 27 days, such as 28 days, for example 29 days, such as 30 days, for example 31 days, such as 32 days, for example 33 days, such as 34 days, for example 35 days, such as 36 days, for example 37 days, such as 38 days, for example 39 days, such as 40 days, for example 41 days, such as
  • the duration of the treatment with said medicament capable of interfering with a component of said Renin-Angiotensin- Aldosteron signalling system is longer than 365 days.
  • Examples of compounds capable of inhibiting A2R signalling include, but are not limited, to the following compounds.
  • the invention relates to the use of compounds capable of binding angiotensin II, including captopril, lisinopril,
  • the invention relates to the use of a compounds capable of binding to the angiotensin Il receptor, such as losartan, irbesartan, valsartan, telmisartan, candesartan, olmesartan, and eprosartan and all compounds capable of angiotensin converting enzyme inhibition, such as captopril, quinapril, benazepril, enalapril, perindopril, fosinopril, lisinopril, trandolapril, and ramipril.
  • a compounds capable of binding to the angiotensin Il receptor such as losartan, irbesartan, valsartan, telmisartan, candesartan, olmesartan, and eprosartan and all compounds capable of angiotensin converting enzyme inhibition, such as captopril, quinapril, benazepril, enalapril, pe
  • Subretinal neovascularization in a much-preferred embodiment of the present invention, the disease in which fibrosis is to be treated or prevented is neovascular age-related macular degeneration.
  • Other diseases where subretinal neovascularization is treatable or preventable with compounds capable of inhibiting fibrosis include myopia, choroidal rupture, choroiditis, angioid streaks, and similar conditions of outer retinal or choroidal injury.
  • the ocular disorder prevented or treated with said medicament is diabetic retinopathy (preproliferative or proliferative diabetic retinopathy) or a disorder associated with diabetic retinopathy, such as macular edema, or a type of neovascular proliferative retinopathy other than proliferative diabetic retinopathy, including, but not limited to, retinal vein occlusion, sickle cell disease, uveitis, retinopathy of prematurity, rubeosis iridis, neovascular glaucoma, or proliferative vitreoretinopathy, traction retinal detachment, or other diseases of the retinal and/or optic nerve characterized by the development of scar tissue within or adjacent to nervous tissue or elsewhere.
  • diabetic retinopathy preproliferative or proliferative diabetic retinopathy
  • a disorder associated with diabetic retinopathy such as macular edema
  • a method for treating and/or preventing intraocular fibrosis, or associated symptoms or complications thereof, in a mammal, including a human being is provided.
  • the method includes the identification of a subject afflicted with intraocular fibrosis or a pathological condition that predisposes to intraocular fibrosis, and the administration of a pharmaceutically acceptable solution containing a pharmaceutically efficient amount of at least one compound capable of inhibiting A2R signalling.
  • the invention relates to a pharmaceutical composition suitable for intravitreal or other intraocular implantation comprising a pharmaceutically effective amount of at least one compound capable of inhibiting A2R signalling, preferably one of the compounds described specifically herein.
  • compositions or medicaments of the present invention comprising compounds capable of inhibiting A2R signalling, include all compositions wherein at least one pharmaceutical compound or composition is contained in an amount effective to achieve its intended purpose.
  • compositions of the present invention may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • Pharmaceutically acceptable carriers may comprise physiologically active com- pounds that act, for example, to stabilize the composition, and/or to increase or decrease the absorption of the agent.
  • Physiologically acceptable compounds may include, for example, carbohydrates, such as glucose, sucrose, or dextrans, including cyclodextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low and/or high molecular weight proteins, compositions that reduce the clearance or hydrolysis of the at least one compound, or excipients or other stabilizers and/or buffers.
  • Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives which are particularly useful for preventing the growth or action of microorganisms.
  • solubilizers and/or emulsifiers are often desired to produce aqueous medicament solutions or emulsions.
  • solubilizers and emulsifiers are well known to those of skill in the art.
  • compositions of the present invention are to be administered preferably to mammalian recipients, most preferably to human beings.
  • the route of administration may be systemic (e.g. oral, parenteral), topical (e.g. eye drops), or local, such as by intravitreal, subretinal, or subtenonal injection or infu- sion.
  • the route of administration is local by intraocular injection or infusion.
  • the at least one compound is in a device formulation held confined by mechanical or physico-chemical effects.
  • the at least one compound is in a slow-release formulation.
  • a person skilled in the art will appreciate that other effective methods of administration are contemplated by the invention.
  • One very preferred embodiment of the present invention comprises administering by intraocular injection at least one active agent in a slow-release device formulation to a subject afflicted with intraocular fibrosis or one or more conditions that predispose to intraocular fibrosis.
  • Dosages and schedules A pharmaceutically efficient amount of at least one compound capable of inhibiting intraocular fibrosis is employed in treatment or prevention of a subject.
  • the dosages and repetition interval (the timing of retreatment) of the drug, in the development of the drug formulation as well as in clinical practice, can be adjusted on the basis of titration tests known to persons skilled in the art.
  • the pharmaceutically efficient amount of the at least one active agent is determined as an amount efficient to diminish, stabilize or restrict in growth the area of the fundus of the eye affected by fibrosis, as assessed objectively or semiobjectively using fundus photography in broad- spectrum or narrow-band photonic radiation, fundus autofluorescence photography at one or more pairs of spectral bands, optical coherence tomography, adaptive optics fundus photography, or other imaging techniques alone or in combination, with or without the use of artificial dyes or contrast agents, including use of post- acquisition computerized data analysis.
  • topographical correlation of retinal function and fundus morphology for instance by microperimetry, electroretinography, photopic perimetry, scotopic perimetry afterimage mapping, white-noise image scotoma mapping and other interactive methods whereby patients themselves can contribute to scotoma mapping with reference to the topography of the retina and other components of the fundus of the eye.
  • mapping fibrosis includes laser-speckle mapping and angiographic mapping of blocked or absent choroidal circulation.
  • the dosage of a pharmaceutical compound or composition of the present invention administered in vivo will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the pharmaceutical effect desired.
  • the ranges of effective doses provided herein are not intended to be limiting and represent preferred dose ranges. However, the most preferred dosage will be tailored to the individual subject, as is understood and determinable by one skilled in the relevant art.
  • An example of the dosage range of a compound required to achieve a clinical effect on fibrosis using systemic administration would be a dosage of 50 mg of losartan twice daily to an adult with a body weight of 70 kg.
  • Another example of the dosage range of a compound required to achieve a clinical effect on intraocular fibrosis using systemic administration would be a dosage of losartan that is sufficient to obtain a reduction in mean arterial blood pressure of at least 10 mmHg in a previously normotensive individual.
  • the formulation may be a water solution.
  • the formulation may comprise a slow-release formulation or device wherein the active agent is held confined by mechanical or physico-chemical effects, including polymer binding, co- polymerization, embedding of the active compound in polymers, gels, solids and other substances, adsorption and other types of non-covalent binding.
  • covalent binding that confers inactivity or sequestration in the bound form together with mechanisms of gradual release that increase or otherwise alter the pharmacokinetic profile of the active agent. Examples of such sustained-release systems include semi-permeable polymer matrices in the form of shaped articles
  • the pharmaceutically active compounds may be crystallized as a salt or salts using any counter-ion that confers to the salt a solubility that is sufficiently rapid or sufficiently slow to provide a desired pharmacokinetic and/or pharmacodynamic profile, as can be determined using conventional kinetics of dissolution assays, microscopic visualization of crystals in the vitreous of the eye, preferably using cross-polarization examination, and dark adaptometric or spectrophotometric examination of the eye.
  • the pharmaceutically active compounds may be attached covalently to a delivery- enhancing transporter by chemical or recombinant methods and referred to as prodrugs in that the release (e.g., by degradation or specific cleavage) of the delivery- enhancing transporters from the drugs results in the conversion of the drug from an inactive to an active form.
  • the pro-drug may be produced by esterification, e.g. as an X-acetonide, where X is an A2R-inhibitor.
  • the drug or pro-drug, or a combination of the two may be crystallized and administered in pure microcrystalline form, in a mixture of crystals with a combination of sizes and coatings that convey a desired and predetermined pharmacokinetic profile and/or susceptibility to disruption by photocoagulation or photodisruptive lasers that may confer lack of drug release or drug release at only low rates before disruption, whereas after non-invasive disruption an increased rate of release from the inactive solid form into water solution inside the eye can be achieved.
  • Example 1 Inhibition of subretinal fibrosis in the eye disease multifocal choroiditis with subretinal fibrosis by concomitant treatment using systemic losartan, systemic prednisolone, and intravitreal ranibizumab.
  • the patient was treated by oral losartan 50 mg bid, prednisolone 50 mg/d, and a single intravitreal injection of ranibizumab 0.5 mg.
  • Significant reduction of foveal thickness was achieved within 24 h. This was accompanied by subjective improvement of paracentral visual function.
  • best-corrected visual acuity had improved to 20/100, the foveal profile as assessed using optical coherence tomography was nearly normal, the new vessels had regressed, and subjective visual function had further improved, yet there was no sign of the prominent subfoveal fibrosis (i.e. subretinal fibrosis under the fovea) that had lead to the severe end-stage in the right eye.
  • SEQ ID NO. 1 Human Angiotensin Il Receptor Subtype AT1
  • SEQ ID NO. 2 Human Angiotensin Il Receptor Subtype AT2 MKGNSTLATTSKNITSGLHFGLVNISGNNESTLNCSQKPSDKHLDAIPILYYIIFVIG
  • SEQ ID NO. 3 Human Angiotensin Converting Enzyme (EC 3.4.15.1 ) LDPGLQPGNFSADEAGAQLFAQSYNSSAEQVLFQSVAASWAHDTNITAEN ARRQEEAALLSQEFAEAWGQKAKELYEPIWQNFTDPQLRRIIGAVRTLGS ANLPLAKRQQYNALLSNMSRIYSTAKVCLPNKTATCWSLDPDLTNILASS RSYAMLLFAWEGWHNAAGIPLKPLYEDFTALSNEAYKQDGFTDTGAYWRS WYNSPTFEDDLEHLYQQLEPLYLNLHAFVRRALHRRYGDRYINLRGPIPA HLLGDMWAQSWENIYDMVVPFPDKPNLDVTSTMLQQGWNATHMFRVAEEF FTSLELSPMPPEFWEGSMLEKPADGREVVCHASAWDFYNRKDFRIKQCTR VTMDQLSTVHHEMGHIQYYLQYKDLPVSLRRGANPGFHEAIGDV
  • SEQ ID NO. 4 Human Renin (EC 3.4.23.15).
  • SEQ ID NO. 5 Human Aldosterone Receptor (Mineralocorticoid receptor)
  • SEQ ID NO. 7 Human Angiotensin 1 DRVYIHPFHL
  • SEQ ID NO. 8 Human Angiotensin 2 DRVYIHPF
  • SEQ ID NO. 10 Human Angiotensin 4 VYIHPF

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Abstract

La présente invention porte sur des composés qui peuvent inhiber une fibrose intra-oculaire et leur utilisation pour le traitement et la prévention d'états qui menacent la fonction visuelle, avec unr concentration particulière sur la prévention et le traitement d'une fibrose sous-rétinienne dans des yeux avec une néovascularisation choroïdale sous-rétinienne secondaire jusqu'à une dégénérescence maculaire liée à l'âge, une myopie, une rupture choroïdienne, une choroïdite, des stries angioïdes de la rétine et des états analogues, et sur la prévention et le traitement d'une fibrose prérétinienne secondaire jusqu'à une rétinophatie proliférative néovasculaire, une occlusion de la veine rétinienne, une drépanocytose, une uvéite, une rétinopathide de prématurité, une vitréorétinopathie proliférante, un décollement de la rétine par traction, une rubéose de l'iris, un glaucome néovasculaire et d'autres maladies de la rétine et/ou du nerf optique caractérisées par le développement d'un tissu cicatriciel dans ou adjacent au tissu nerveux ou ailleurs.
PCT/DK2008/050107 2007-05-14 2008-05-14 Prévention d'une fibrose intra-oculaire WO2008138350A1 (fr)

Applications Claiming Priority (4)

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DKPA200700725 2007-05-14
US94702507P 2007-06-29 2007-06-29
US60/947,025 2007-06-29

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040227A2 (fr) * 1999-01-05 2000-07-13 University Of Utah Procedes de traitement d'etats associes a l'accumulation d'un excedent de matrice extracellulaire
WO2003079978A2 (fr) * 2002-03-18 2003-10-02 Beth Israel Deaconess Medical Center Activite de protease de la thrombine pour inhiber l'angiogenese
WO2004041155A2 (fr) * 2002-05-13 2004-05-21 Children's Hospital Los Angeles Traitement et prevention d'une formation de cicatrices anormales dans des cheloides et d'autres blessures ou lesions cutanees ou internes
WO2008058383A1 (fr) * 2006-11-13 2008-05-22 Chronogen Inc. Inhibiteurs d'acat et leur utilisation dans la prévention ou le traitement de la fibrose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040227A2 (fr) * 1999-01-05 2000-07-13 University Of Utah Procedes de traitement d'etats associes a l'accumulation d'un excedent de matrice extracellulaire
WO2003079978A2 (fr) * 2002-03-18 2003-10-02 Beth Israel Deaconess Medical Center Activite de protease de la thrombine pour inhiber l'angiogenese
WO2004041155A2 (fr) * 2002-05-13 2004-05-21 Children's Hospital Los Angeles Traitement et prevention d'une formation de cicatrices anormales dans des cheloides et d'autres blessures ou lesions cutanees ou internes
WO2008058383A1 (fr) * 2006-11-13 2008-05-22 Chronogen Inc. Inhibiteurs d'acat et leur utilisation dans la prévention ou le traitement de la fibrose

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Diabetic retinopathy candesartan trials (DIRECT)", 10 November 2005 (2005-11-10), XP002492102, Retrieved from the Internet <URL:http://www.clinicaltrials.gov/ct2/show/NCT00252733?term=candesartan+retinopathy&rank=3> [retrieved on 20080813] *
MORAVSKI, C.J. ET AL.: "Retinal neovascularization is prevented by blockade of the renin-angiotensin system", HYPERTENSION, vol. 36, 2000, pages 1099 - 1104, XP002492101 *

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