Compositions and methods of treating diabetic retinopathy

Patent metadata

Field	Value
Publication number	US-10898516-B2
Application number	US-201916399604-A
Country	US
Kind code	B2
Filing date	Apr 30, 2019
Priority date	Jun 4, 2014
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

A method of treating diabetic retinopathy in a subject in need thereof includes administering to the subject a therapeutically effective amount of one or more agents that act as a trap of reactive aldehydes and/or inhibit diabetes-induced superoxide generation and capillary degeneration regulated by GPCR signaling pathways.

First claim

Having described the invention, we claim:

1. A method of treating retinal capillary degeneration in a subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of one or more agent that inhibits or antagonizes the Gs signaling cascade in a retina cell or agent that activates Gi signaling in a retina cell to inhibit superoxide generation and capillary degeneration.

2. The method of claim 1 , comprising administering to the subject a therapeutically effective amount at least two of an agent that inhibits and/or antagonizes the Gq signaling cascade in a retina cell, an agent that inhibits or antagonizes the Gs signaling cascade in a retina cell or an agent that activates Gi signaling cascade in a retina cell.

3. The method of claim 2 , comprising administering to the subject a therapeutically effective amount at least three or more of an agent that inhibits and/or antagonizes the Gq signaling cascade in a retina cell, an agent that inhibits or antagonizes the Gs signaling cascade in a retina cell and an agent that activates Gi signaling cascade in a retina cell.

4. The method of claim 1 , the agent comprising at least one of an alpha 1 adrenergic receptor (α 1 -AR) antagonist, a PLC inhibitor, an IP 3 receptor inhibitor, an inhibitor Ca+accumulation in mitochondria, a NADPH oxidase inhibitor, a 5-HT 2a receptor antagonist, a 5-HT 2b receptor antagonist, a 5-HT 2c receptor antagonist, a 5-HT 2a/c receptor antagonist, a 5-HT 4 receptor antagonist, a 5-HT 6 receptor antagonist, 5-HT 7 receptor antagonist, andenylyl cyclase inhibitor, an M3 receptor antagonist, an alpha-2 adrenergic receptor agonists, or a PKA activator.

5. The method of claim 1 , the agent comprising one or more alpha 1 adrenergic receptor antagonists.

6. The method of claim 5 , the alpha 1 adrenergic receptor antagonists comprising at least one of doxazosin, prazosin, tamsulosin, terazosin, phenxoxybenzamine, and 5-methylurapadil.

7. The method of claim 1 , the agent comprising one or more serotonin receptor antagonists selected from the group consisting of a 5-HT 2a receptor antagonist, a 5-HT 2b receptor antogonist, a 5-HT 2c receptor antagonist, a 5-HT 2a/c receptor antagonist, a 5-HT 4 receptor antagonist, a 5-HT 6 receptor antagonist, and a 5-HT 7 receptor antagonist.

8. The method of claim 7 , the serotonin receptor antagonist being selected from the group consisting of agomelatine, pizotifen, RS 23579-190, Ro 04-6790 (4-Amino-N-[2,6-bis(methylamino)-4-pyrimidinyl]benzenesulfonamidev), SGS 518 oxalate (1-methyl-3-(1-methyl-4-piperidyl)indol-5-yl] 2,6-difluorobenzenesulfonate; oxalic acid), SB 269970 (3-({(2R)-2-[2-(4-Methyl-1-piperidinyl)ethyl]-1-pyrrolidinyl}sulfonyl)phenol hydrochloride (1:1)), LY 215840 ((8β)-N-[(1S,2R)-2-Hydroxycyclopentyl]-1-isopropyl-6-methylergoline-8-carboxamide), citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, femoxetine, clomipramine, combinations thereof, and pharmaceutically acceptable salts thereof.

9. The method of claim 1 , the agent comprising an adenylyl cyclase inhibitor.

10. The method of claim 9 , the adenylyl cyclase inhibitor comprising 9-tetrahydrofuryl adenine, 2′,5′-dideoxyadenosine, or 9-(cyclopentyl)-adenine.

11. The method of claim 1 , the agent comprising a phospholipase C (PLC) inhibitor.

12. The method of claim 1 , the agent being delivered to the subject by at least one of topical administration, systemic administration, intravitreal injection, and intraocular delivery.

13. The method of claim 1 , the agent being provided in an ocular preparation for sustained delivery.

14. The method of claim 1 , the agent is from the group consisting of:
3-Aminomethyl-5-methylhexanoic acid; 3-Aminomethyl-5-methylheptanoic acid; 3-Aminomethyl-5-methyl-octanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-methyl-undecanoic acid; 3-Aminomethyl-5-methyl-dodecanoic acid; 3-Aminomethyl-5-methyl-tridecanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-trifluoromethyl-hexanoic acid; 3-Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(phenylmethyl)-hexanoic acid; (S)-3-(Aminomethyl)-5-methylhexanoic acid; (R)-3-(Aminomethyl)-5-methylhexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; 3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; (3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; 3-Aminomethyl-4-isopropyl-hexanoic acid; 3-Aminomethyl-4-isopropyl-heptanoic acid; 3-Aminomethyl-4-isopropyl-octanoic acid; 3-Aminomethyl-4-isopropyl-nonanoic acid; 3-Aminomethyl-4-isopropyl-decanoic acid; 3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoro-propoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid;

Assignees

• Univ Case Western Reserve
• Case Western Univ

Inventors

• Palczewski Krzysztof
• Kern Timothy

Classifications

• A61K31/352

  condensed with carbocyclic rings, e.g. methantheline  {(cannabinoids A61K31/658)} · CPC title

• A61K31/13 Primary

  Amines {(A61K31/04 takes precedence)} · CPC title

• A61K51/0402 Primary

  carboxylic acid carriers, fatty acids (amino acids A61K51/0406) · CPC title

• A61K31/155

  Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2) · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title