US 20030199551A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0199551A1 Dreyer (43) Pub. Date: Oct. 23, 2003

(54) CALCIUM BLOCKERS TO TREAT (60) Provisional application No. 60/051,962, filed on Jun. PROLIFERATIVE WITREORETINOPATHY 30, 1997. (76) Inventor: Evan B. Dreyer, Pittsburgh, PA (US) Publication Classification Correspondence Address:

(51) Int. Cl." ...... A61K 31/445; A61K 31/455 ROBERT.J. BARAN Allergan, Inc. (T2-7H) (52) U.S. Cl...... 514/317; 514/355 2525 Dupont Drive Irvine, CA 926.12 (US) (57) ABSTRACT (21) Appl. No.: 10/436,902 Glutamate causes migration and proliferation of retinal (22) Filed: May 12, 2003 pigment epithelium and/or glial cells, and glutamate antago Related U.S. Application Data nists can prevent, treat or reduce retinal pigment epithelium and/or glial migration and the Subsequent development of (63) Continuation of application No. 10/038,215, filed on proliferative Vitreoretinopathy. Avoidance or management of Jan. 2, 2002, now Pat. No. 6,573,280, which is a continuation of application No. 09/445,832, filed on proliferative vitreoretinopathy can be achieved by adminis Dec. 13, 1999, now Pat. No. 6,380,261, filed as 371 tering to the patient a compound capable of reducing of international application No. PCT/US98/12414, glutamate-induced retinal cell migration in a concentration filed on Jun. 15, 1998. effective to reduce Such migration. US 2003/0199551A1 Oct. 23, 2003

CALCIUM BLOCKERS TO TREAT 0007. A third aspect of the invention features treating PROLIFERATIVE WITREORETINOPATHY preventing or reducing proliferative vitreoretinopathy in a patient by administering to the patient's retina an effective CROSS REFERENCE TO RELATED PATENT amount of a compound that reduces glutamate related retinal APPLICATIONS cell migration, proliferation, or both. 0001. This patent application is a continuation of U.S. 0008. The compound may be one of the so-called NMDA patent application Ser. No. 09/445,832 which was filed on antagonists-i.e., it reduces neuronal damage mediated by Dec. 13, 1999 as the U.S. National Patent Application of the NMDA receptor complex. Alternatively, the compound PCT/US98/12414, which was filed on Jun. 15, 1998 and was antagonizes neuronal damage mediated by the Voltage based on U.S. Provisional Application No. 60/051,962, dependent . Other useful compounds are which was filed on Jun. 30, 1997 in the name of Dreyer. those which limit release of glutamate from cells or reduce BACKGROUND OF THE INVENTION the intracellular neurotoxic consequences of glutamate inter 0002 This application relates to preventing, controlling action with cell membrane glutamate receptorS. Preferably, reducing and/or treating proliferative vitreoretinopathy. Pro the compound crosses the blood-retinal barrier. liferative vitreoretinopathy (including epiretinal membrane 0009. The patient may be anyone who has experienced, formation) is a potentially devastating ophthalmic condition or is at risk for experiencing, penetrating trauma, retinal tear, that can lead to blindness. It can develop after any penetra traction detachment, Vitrectomy, or intraocular Surgery. The tion of the eye-Surgical or traumatic. Predisposing condi compound may be administered to the patient topically, tions therefore include, but are not limited to, penetrating orally, or intravitreally, as well as by other routes described trauma, retinal tears, traction detachments, vitrectomy, and below. It may be administered chronically, i.e., over an intraocular Surgery. Any ophthalmic condition that precipi extended period of a month or even six months or years. tates or permits migration of retinal pigment is epithelium or 0010) The invention preferably will be used to treat glial cells can lead to the development of proliferative patients having proliferative vitreoretinopathy or to treat vitreoretinopathy. See Machamer (1978) British J. Ophthal. patients prophylactically to avoid that condition. Preferably, 62:737; Hilton et al. (1983) Ophthalmology 90:121. the agent is administered over an extended period (e.g., at SUMMARY OF THE INVENTION least six-months and preferably at least one year). Those at 0003) 1 have discovered that glutamate causes migration risk for developing proliferative vitreoretinopathy include and proliferation of retinal pigment epithelium and/or glial patients who have experienced penetrating trauma, retinal cells. The invention features the use of glutamate antagonists tears, traction detachments, Vitrectomy, or intraocular Sur to reduce or control retinal pigment epithelium and/or glial gery. migration and the Subsequent development of proliferative 0011 Particularly preferred compounds are antagonists Vitreoretinopathy. Avoidance or management of proliferative of the NMDA receptor-channel complex. The term “NMDA Vitreoretinopathy can be achieved by administering to the receptor antagonists' includes several sub-types of NMDA patient a compound capable of reducing glutamate-induced antagonists including: a) channel blockers—i.e., antagonists retinal pigment epithelium and/or glial migration in a con that operate uncompetitively to block the NMDA receptor centration effective to reduce Such migration. channel; b) receptor antagonists-antagonists that compete 0004 While I do not wish to be bound to any specific with NMDA to act at the NMDA binding site; c) agents theory, I conclude that one or more of the Several types of acting at either the glycine co-agonist Site or any of Several calcium-permeable CNS ion channels mentioned below can modulation Sites Such as the Zinc Site, the site, be involved in controlling Such migration, including: a) the the redox modulatory site, or the polyamine site; d) agents various aspects of the NMDA (N-methyl-D-aspartate) which inhibit the downstream effects of NMDA receptor receptor channel complex; b) the voltage-dependent Ca" Stimulation, Such as agents that inhibit activation of protein channels; and c) other channels directly coupled to kinase C activation by NMDA stimulation, antioxidants, and glutamate (or excitatory amino acid) receptors. Such chan agents that decrease phosphatidylinositol metabolism. nels are reviewed in: Sommer, B. and Seeburg, P. H. 0012. Other compounds that are useful in the invention “Glutamate receptor channels: novel properties and new include Voltage-dependent calcium channel antagonists, e.g. clones'Trends Pharmacological Sciences 13:291-296 those which exert a Substantial direct effect on glutamate (1992); Nakanishi, S., “Molecular Diversity of glutamate toxicity mediated by the L-type voltage dependent Ca" receptors and implications for brain function”, Science channel in that they produce a Statistically significant result 248:597-603 (1992). in experiments measuring glutamate induced effects by the 0005 One aspect of the invention generally features a general method described in Karschian and Lipton, J. method of treating, preventing, or reducing proliferative Physiol. 418: 379-396 (1989) or by other techniques for Vitreoretinopathy in a patient by administering to the measuring antagonism of the L-type Ca" channel known to patient's retina an effective amount of a compound that those in the art. (We contrast the direct effect so measured reduces CNS neuronal damage incident to (associated with) with the secondary effects of excitoxicity mediated by other is calcium ion influx. channels, which in turn causes flow through the Voltage dependent Ca" channels.) Particular candidate compounds 0006 A second aspect of the invention features treating, include Class I Voltage dependent Ca" channel antagonists, preventing, or reducing proliferative vitreoretinopathy in a e.g., phenylalkylamines. patient by administering to the patient's retina an effective amount of at least one of the compounds listed in one or 0013 Preferably, the compounds used cross the blood more of Tables 2-5. below. retina barrier and can be administered chronically. Other US 2003/0199551A1 Oct. 23, 2003 useful agents act as antagonists of non-NMDA receptors tures antagonists having certain specific characteristics: the (glutamate receptor types other than the NMDA receptor ability to cross the blood-retina barrier; and the ability to be complex discussed above), and include agents which block administered chronically. Within those guidelines, any Suit inotropic glutamate receptorS or interact with metabotropic able antagonist of the glutamate induced excitotoxicity may glutamate receptors (Nakanishi, Supra). Still other agents act be used in accordance with the invention. AS mentioned, in to limit (reduce) release of glutamate from cells, thereby preferred embodiments, N-methyl-D-aspartate (NMDA) acting upstream from the glutamate receptors in the excita Subtype of glutamate receptor-channel complex may be used tory neurotoxicity process. Still other agents may act by to reduce or prevent proliferative vitreoretinopathy-related blocking downstream effects of glutamate receptor Stimula injury. Many antagonists of the NMDA receptor have been tion, e.g., the intracellular consequences of glutamate inter identified (Watkins et al., Trends in Pharmacological Sci. action with a cell membrane glutamate receptor, Such as 11:25, 1990, hereby incorporated by reference). There are agents (like dantrolene) that block the rise in intracellular Several recognized Sub-types of NMDA receptor including: calcium following Stimulation of membrane glutamate a) channel blockers—i.e., antagonists that operate non receptors. competitively to block the NMDA receptor channel; b) 0.014. The most preferred compounds are those capable receptor antagonists-antagonists that compete with of crossing the blood-retinal barrier; these compounds may NMDA, acting at the NMDA binding site; c) agents acting be administered orally, intravenously, or topically and croSS at either the glycine co-agonist Site or any of Several intervening barriers including the blood-retina barrier to modulation Sites Such as the Zinc Site, the magnesium site, reach the retinal ganglion cells. Compounds that do not the redox modulatory site, or the polyamine site; d) agents freely cross the blood-retina barrier are leSS preferred; these which inhibit the downstream effects of NMDA receptor compounds may be administered intravitreally to the retina. Stimulation Such as agents that inhibit activation of protein In the case of compounds that have an intermediate ability kinase C activation by NMDA stimulation, antioxidants, and to croSS the blood-retina barrier, the mode of administration agents that decrease phosphatidylinositol metabolism. will depend on the dosage required and other factors. 0019. Other compounds that are useful in this invention 0.015 Among the preferred compounds are amantadine include non-NMDA receptor antagonists, Such as agents is derivatives (e.g., memantine, amantadine, and rimantadine), which block other types of inotropic glutamate receptorS or nitroglycerin, dextorphan, , and interact with metabotropic glutamate receptors, Voltage CGS-19755. See generally, the compounds listed in Table 2. dependent calcium channel antagonists (against L, N, T, and P type channels) (Bean, B. P. Annu. Rev. Physiol. 51:367 0016. The invention is useful for the reduction or pre 384 (1989); Hess, P. Annu. Rev. Neurosci. 13:337-356 vention (including prophylactic treatment) of damage as a (1990)), and are described in greater detail below; and result of proliferative vitreoretinopathy Other features and agents which act to decrease the release of glutamate, advantages of the invention will be apparent from the thereby acting upstream in the excitatory neurotoxicity following description of the preferred embodiments thereof, proceSS. and from the claims. 0020 Table 1, below, lists various suitable NMDA and DESCRIPTION OF THE PREFERRED non-NMDA receptors which do not operate via the voltage EMBODIMENTS dependent Ca" . Tables 2-4 list antagonists of the voltage dependent Ca" channel, which can be used by 0017 Selection of Antagonists themselves in connection with the first aspect of the inven 0.018. In view of our discovery that glutamate is associ tion, and which can also be used in combination with other ated with proliferative vitreoretinopathy, the invention fea antagonists in the Second aspect of the invention.

TABLE 1. NMDA Antagonists NMDA Antagonists NMDA Antagonists 1. Competitive NMDA Antagonists (act 2. Channel Blockers (Un-Competitive 3. Antagonists at Glycine Site of the at agonist binding site) NMDA Antagonists) NMDA Receptor CGS-19755 (CIBA-GEIGY) and other MK-801 (Dizocilpine) and other Kynurenate, 7-chloro-kynurenate, 5,7- piperidine derivatives, D-2-amino-5- derivatives of dibenzyocycloheptene chloro-kynurenate, thio-derivatives, and phosphovalerate, D-2-amino-7- (Merck) other derivatives. (Merck) phosphonoheptanoate (AP7) CPP (3-(2-carboxypiperazin-4-y-propyl Sigma receptor ligands, e.g. Dextrorphan, Indole-2-carboxylic acid 1-phosphonic acid) dextromethorphan and morphinan derivatives (Hoffman La Roche) such as and rimcazole (which also block calcium channels) LY274614, CGP39551, CGP37849, , Tiletamine and other DNOX LY233053, LY233536 cyclohexanes O-phosphohomoserine Phencyclidine (PCP) and derivatives, and Quinoxaline or Oxidiazole derivatives pyrazine compounds including CNQX, NBQX MDL100,453 Memantine, amantadine, rimantadine and Glycine partial agonist (e.g. Hoecht derivatives Roussel P-9939) CNS 1102 (and related bi- and tri substituted guanidines) Diamines US 2003/0199551A1 Oct. 23, 2003

TABLE 1-continued Conantokan peptide from Conus geographus Agatoxin-489 NMDA Antagonists NMDA Antagonists NMDA Antagonists 4. Polyamine Site of NMDA Receptor 5. Redox Site of NMDA Receptor 6. Other Non-Competitive NMDA Antagonists Arcaine and related biguanidines and Oxidized and reduced glutathione Hoechst 831917189 biogenic polyamines and related drugs PQQ (pyrroloquinoline quinone) SKB Carvedillol Diethylenetriamine SL 82,0715 Compounds that generate Nitric Oxide (NO) or other oxidation states of nitrogen monoxide (NO+, NO-) including those listed in the box below 1,10-diaminodecane (and related inverse Nitroglycerin and derivatives, Sodium agonists) Nitroprusside, and other NO generating listed on p. 5 of this table Nitric oxide synthase (NOS) Inhibitors: Arginine analogs including N-mono-methyl L-arginine (NMA); N-nitro-L-arginine (NNA); N nitro-L-arginine methyl ester; N-iminoethyl L-ornithine Flavin Inhibitors: diphenyliodinium; Calmodulin inhibitors, trifluoperizine Calcineurin Inhibitors, e.g., FK-506 (inhibits calcineurin and thus NOS diphosphoxylase) Inhibitors of Downstream Inhibitors of Downstream Non-NMDA Receptor Effects of NMDA Effects of NMDA Antagonists 7. Agents to inhibit protein kinase C 8. Downstream effects from Receptor 9A. Non-NMDA antagonists activation by NMDA stimulation Activation (Competitive) (involved in NMDA toxicity) MDL 27,266 (Merrill Dow) and triazole 8a. To decrease phopshatidylinositol CNOX, NBOX, YM900, DNOX, one derivatives metabolism PD140532 Monosialogangliosides (eg GM1 of Fidia kappa opioid receptor agonist: AMOA (2-amino-33-9carboxymethoxyl Corp.) and other ganglioside derivatives U50488 (Upjohn) and dynorphan 5-methoxylisoxazol-4-ylpropionate LIGA20, LIGA4 (may also effect calcium extrustion via calcium ATPase) kappa opioid receptor agonist: PD117302, 2-phosphophonoethyl phenylalanine CI-977 derivatives, i.e. 5-ethyl, 5-methyl, 5 trifluoromethyl 8b. To decrease hydrogen peroxide and free radical injury, eg antioxidants 21-aminosteroid (lazoroids) such as 9B. Non-NMDA Non competitive U74500A, U75412E and U74005F antagonists U74389F, FLE26749, Trolox (water GYK152466 soluble alpha tocophenol), 3,5-dialkoxy-4- hydroxy-benzylamines Compounds that generate Nitric Oxide Evans Blue (NO) or other oxidation states of nitrogen monoxide (NO+, NO-) including those listed in the box below Nitroglycerin and derivatives, Sodium Nitroprusside, and other NO generating listed on p. 5 of this table Nitric oxide synthase (NOS) inhibition: Arginine analogs including N-mono methyl-L-arginine (NMA); N-amino-L- arginine (NAA); N-nitro-L-arginine methyl ester; N-iminoethyl-L-ornithine Agents Active at Drugs to decrease intracellular Metabotropic Glutamate calcium following glutamate Receptors Decrease glutamate release receptor stimulation 10a. Blockers of Metabotropic 11. Agents to decrease glutamate release 12a. Agents to decrease intracellular cadium Glutamate Receptors release AP3 (2-amino-3-phosphonoprionic acid) Adenosine, and derivatives, e.g. Dantrolene (sodium dantrium); Ryanodine cyclohexyladenosine (or ryanodine + caffiene) 10b. Agonists of Metabotropic CNS1145 12b. Agents inhibiting intracellular Calcium Glutamate Receptors ATPase (1S,3R)-1-Amino-cyclopentane-1,3- Conopeptides: SNX-111, SNX-183, SNX Thapsigargin, cyclopiazonic acid, BHQ dicarboxylic acid (1S,3R)-ACPD). 230 (2,5-di-(tert butyl)-1,4-benzohydroquinone; commonly ref as trans-ACPD 2-5-di-(tert-butyl)-1,4-benzohydroquinone) US 2003/0199551A1 Oct. 23, 2003

TABLE 1-continued Omega-Aga-IVA, toxin from venom of funnel web spider Compounds that generate Nitric Oxide (NO) or other oxidation states of nitrogen monoxide (NO+, NO-) including those listed in the box below Nitroglycerin and derivatives, Sodium Nitroprusside, and other NO generating listed on p. 5 of this table Nitric oxide synthase (NOS) Inhibitors: Arginine analogs including N-mono methyl-L-arginine (NMA); N-amino-L- arginine (NAA); N-nitro-L-arginine (NNA); N-nitro-L-arginine methyl ester; N-iminoethyl-L-ornithine Additional NO-generating compound Isosorbide dinitrate (isordil) S-nitrosocaptopril (Snocap) Serum albumin coupled to nitric oxide (SA-NO) Cathepsin coupled to nitric oxide (cathepsin-NO) Tissue plasminogen activator coupled to NO (TPA-NO) SIN-1 (also known as SIN1 or molsidomine) Ion-nitrosyl complexes (e.g., nitrosyl-iron complexes, with iron in the Fe2+ state)

0021) TABLE 3-continued

DIHYDROPYRIDINE CALCIUM CHANNEL ANTAGONSTS Antogonist of the Voltage Dependent Calcium Channels (N, L., T., P and other types floridine MDL72567 Ro18-3981 dihydropyridines (e.g., ) DHP-218 phenylalkylaminesD-888) (e.g., , (S)-, D-600, nimodipine benzothiazepines (e.g., and others) and related drugs 8363-S diphenylbutylpiperdines PN200-110 () iodipine diphenylpiperazines (e.g., ? CV4093 azidopine series) HOE 166 and related drugs fluspirilene and related drugs toxins and natural compounds (e.g., snail toxins - 0023 coconotoxin GVIA and GVIIA, , taicatoxin, tetrandine, helolena toxin, plectreurys toxin, funnel-web spider venom and its toxin fraction, TABLE 4 agatoxins including co-agatoxin IIIA and co-agatoxin IVA. OTHER CALCIUM CHANNEL ANTAGONSTS diclofurime D-600 D-888 0022) SmithKline 9512 ranolzine TABLE 3 mioflazine CERM-11956 flunarizinefcinnarizine R-58735 DIHYDROPYRIDINE CALCIUM CHANNEL ANTAGONSTS series R-56865 ifedipi KW3O49 Verapamil nitedlpine dilfiazine henwtoin dipropervine Rise EYs () SP (S)-emopamil tricyclic antidepressents meSudlpine GX 1048 YM-09730-5 or (4S)DHP US 2003/0199551A1 Oct. 23, 2003

0024. In Vitro Assay 0030. Other embodiments are within the following 0.025. An antagonist may be tested for utility in the claims. method of the invention by monitoring its effect on prolif What is claimed is: erative retinopathy as follows. Cultured fibroblasts will be 1. A method of treating, preventing, or reducing prolif injected into the vitreous of the rabbit eye. After two weeks, erative Vitreoretinopathy in a patient by administering to the the degree of Vitreopathy can be assessed histologically. At patient's retina an effective amount of a compound that the time of the initial insult, the animals will be treated with reduces CNS neuronal damage incident to calcium ion the compound under consideration. Such models are well influx. known. A few examples (hereby incorporated by reference) 2. A method of treating or preventing proliferative vitreo included Kiumura et al. Human Gene Therapy, 7: 799-808 retinopathy in a patient by administering to the patient's (1996); Sakamoto et al., Ophthalmology 102:1417-1421 retina an effective amount of at least one of the compounds (1995); Handa et al. Experimental Eye Research 62:689-696 listed in one or more of Tables 1-4. (1996); Berger et al. 37: 2318-1325 (1996); de Souza et al. 3. A method of treating or preventing proliferative vitreo Ophthalmologica 209: 212-216 (1995); Nakagawa et al. retinopathy in a patient by administering to the patient's Ophthalmnology & Visual Science 36:2388-2395 (1995); retina an effective amount of a compound that reduces Steinhorst et al. Archive for Clinical & Experimental Oph glutamate related retinal cell migration, proliferation, or thalmology 232:347-354 (1994). both. 0026. Use 4. The method of claim 1, 2, or 3 in which the compound inhibits glutamate-related proliferation of retinal cells. 0027. An effective receptor antagonist will cause a 5. The method of claim 1, 2, or 3 in which the compound decrease in proliferative vitreoretinopathy. AS described inhibits glutamate-related migration of retinal cells. above, the preferred compounds which croSS the blood 6. The method of claim 1, 2, or 3 in which the compound retinal barriers are preferably administered topically or controls NMDA receptor complex-mediated activity. orally in known, physiologically acceptable vehicles includ 7. The method of claim 1, 2, or 3 in which the compound ing tablets, liquid excipients and Suspensions. Those skilled controls the Voltage-dependent calcium channel activity. in the art will appreciate how to formulate acceptable 8. The method of claim 1, 2, or 3 in which the compound therapeutics. crosses the blood-retinal barrier. 0028 Antagonists may be compounded into a pharma 9. The method of claim 1, 2, or 3 in which the patient has ceutical preparation, using pharmaceutical compounds well or will experience penetrating trauma, retinal tear, traction known in the art; the exact formulation and dosage of the detachment, vitrectomy, or intraocular Surgery. antagonist compound depends upon the route of adminis 10. The method of claim 1, 2, or 3, said compound being tration. Generally, the effective daily dose of the antagonists administered to Said patient topically. will range from 0.01 to 1000 is mg/kg. 11. The method of claim 1, 2, or 3, Said compound being administered to Said patient orally. Other Emodiments 12. The method of claim 1, 2, or 3, Said compound being 0029. Other embodiments are within the following administered to Said patient intravitreally. claims. In the method of the invention, a useful compound 13. The method of claim 1 or 2 wherein said is compound may be administered by any means that allows the com is administered chronically. pound access to the retina. The compounds useful in the 14. The method of claim 1, 2, or 3 wherein said compound method include antagonists of excitatory amino acid recep limits release of glutamate from cells. tors (both NMDA and non-NMDA subtypes) that act to 15. The method of claim 1, 2 or 3, wherein said compound reduce retinal cell migration or proliferation or reduce controls glutamate interaction with cell membrane binding of glutamate to the NMDA receptor. The antagonists glutamate receptors. can act at a modulatory site or a co-agonist Site or by blocking the chain of events initiated by receptor activation.