Pharmacology of Visual Cycle Modulators

• US 20110003895A1
• Filed: 07/02/2010
• Published: 01/06/2011
• Est. Priority Date: 07/02/2009
• Status: Active Grant

• Current Assignee: Acucela Inc. (Kubota Pharmaceutical Holdings Co. Ltd.)
• Original Assignee: Acucela Inc. (Kubota Pharmaceutical Holdings Co. Ltd.)
• Inventors: Scott, Ian L., Boman, Nancy, Bavik, Claes, Kubota, Ryo
• Granted Patent: US 10,471,027 B2
• Time in Patent Office: Days
• US Class Current: 514/570
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Described herein are methods for the treatment of an ophthalmic disease or disorder comprising the administration of non-retinoid visual cycle modulators.

Claims

1. A method of treating an ophthalmic disease or disorder comprising administration of a non-retinoid compound resulting in a normalized electroretinogram response from about 5% to about 55% after about 12 hours to about 48 hours post administration of said non-retinoid compound.

2. The method of claim 1 wherein the normalized electroretinogram response is from about 5% to about 15%, from about 15% to about 25%, from about 25% to about 35%, or from about 35% to about 55%.

6. The method of claim 1 wherein the normalized electroretinogram response is determined after about 12 hours to about 16 hours, after about 16 hours to about 20 hours, after about 20 hours to about 24 hours, after about 24 hours to about 30 hours, after about 30 hours to about 36 hours, after about 36 hours to about 42 hours, post administration of said non-retinoid compound.

21. The method of claim 1 wherein non-retinoid compound is orally administered.

22. The method of claim 1 wherein non-retinoid compound is administered in the morning, is administered upon waking from sleep, or is administered upon waking from sleep in the morning.

25. The method of claim 1 wherein the non-retinoid compound is selected from a compound of Formula (I) or a tautomer, stereoisomer, geometric isomer or pharmaceutically acceptable solvate, hydrate, salt, polymorph, N-oxide or prodrug thereof:

26. The method of claim 25 wherein the compound of Formula (I) has the structure of Formula (II):

27. The method of claim 26 wherein the compound of Formula (II) is further defined as

R¹ and R² are each independently selected from hydrogen, halogen, C₁-C₅ alkyl, or —

OR⁶;

R⁹ and R¹⁰ are each independently selected from hydrogen, halogen, alkyl, or —

OR¹⁹;

or R⁹ and R¹⁹ together form an oxo;

R⁶ and R¹⁹ are each independently hydrogen or alkyl;

R¹⁶ and R¹⁷, together with the carbon to which they are attached form a carbocyclyl; and

R¹⁸ is selected from a hydrogen, alkoxy or hydroxy.

28. The method of claim 27 wherein the compound of Formula (II) is further defined as R¹⁶ and R¹⁷, together with the carbon to which they are attached, form a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and R¹⁸ is hydrogen or hydroxy.

29. The method of claim 28 wherein the compound of Formula (II) (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol.

30. The method of claim 29 wherein the dose is from about 4 mg to about 100 mg.

31. The method of claim 29 wherein the dose is about 5 mg, about 7 mg, about 20 mg, about 40 mg, about 60 mg, or about 75 mg.

41. The method of claim 1 wherein the ophthalmic disease or disorder is selected from retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby'"'"'s fundus dystrophy, optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, ischemia reperfusion related retinal injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby'"'"'s fundus dystrophy, uveitis, a retinal injury, a retinal disorder associated with Alzheimer'"'"'s disease, a retinal disorder associated with multiple sclerosis, a retinal disorder associated with Parkinson'"'"'s disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, myopia, and a retinal disorder associated with AIDS.

42. The method of claim 41 wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt'"'"'s macular dystrophy.

43. The method of claim 42 wherein the ophthalmic disease or disorder is dry age-related macular degeneration.

44. The method of claim 41 wherein the ophthalmic disease or disorder is diabetic retinopathy.

45. The method of claim 1 wherein the cone response amplitude remains within about 10%, within about 20%, or within about 30% of the pre-treatment amplitude.

48. The method of or 16claim 1 wherein the treatment results in no noticeable deficiency in night vision.

49. The method of claim 1 wherein the dosage of non-retinoid compound is adjusted to provide no noticeable deficiency in night vision.

50. The method of claim 1 wherein the method results in no noticeable loss in photopic vision.

51. The method of claim 1 wherein the method results in no detectable effect on sensitivity in photopic conditions.

52. The method of claim 1 wherein the non-retinoid compound, or tautomer, stereoisomer, geometric isomer, pharmaceutically acceptable solvate, hydrate, salt, polymorph, N-oxide or prodrug thereof, is selected from the group consisting of:

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13. A method of treating an ophthalmic disease or disorder comprising administration of a single dose of a non-retinoid compound resulting in a greater normalized electroretinogram response on day 1 than on day 2.

14. A method of treating an ophthalmic disease or disorder comprising administration of a non-retinoid compound resulting in a greater therapeutic response on day 2 than on day 1 after the administration of a single dose.

15. The method of claim 14 wherein the therapeutic response is determined by electroretinography.

16. A method of treating an ophthalmic disease or disorder comprising administration of a non-retinoid compound resulting in a normalized electroretinogram response less than about 50% for a time period of about 4 hours to about 36 hours, about 4 hours to about 10 hours, about 10 hours to about 16 hours, about 16 hours to about 24 hours, or about 24 hours to about 36 hours after the plasma concentration of said non-retinoid compound has declined to 0.3 C_max.

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37. A method of determining the dose to be administered for the treatment of an ophthalmic disease or disorder by administration of a non-retinoid visual cycle modulator comprising determining the normalized electroretinogram response from about 12 hours to about 48 hours after the administration of a single dose of said non-retinoid visual cycle modulator.

38. A controlled-release solid dosage form for the treatment of an ophthalmic disease or disorder comprising a compound of Formula (I) wherein the plasma T_max is observed 12 hours post-dose.

39. A dosing schedule for the treatment of an ophthalmic disease or disorder comprising a drug holiday after from about 3 months of continuous daily dosing to about 12 months of continuous daily dosing.

40. The dosing schedule of claim 39 wherein the drug holiday is a time period of from about 3 days to about 21 days.

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