Therapeutic drug for diseases related to endoplasmic reticulum cell death in corneal endothelium

Patent metadata

Field	Value
Publication number	US-2022296580-A1
Application number	US-202217831843-A
Country	US
Kind code	A1
Filing date	Jun 3, 2022
Priority date	Oct 31, 2013
Publication date	Sep 22, 2022
Grant date	—

Abstract

The present invention provides a treatment drug or prophylactic drug for diseases, disorders, or conditions related to endoplasmic reticulum (ER) stress. Specifically, the present invention provides a treatment drug or prophylactic drug for diseases, disorders, or conditions related to endoplasmic reticulum (ER) stress in the corneal epithelium, the drug containing a TGFβ-signal inhibitor. As a preferred TGFβ-signal inhibitor, the drug contains 4-[4-(1,3-benzodioxole-5-yl)-5-(2-pyridinyl)-1H-imidazole-2-yl]benzamide.

First claim

1 . A method of treating or preventing a disease, disorder or condition associated with endoplasmic reticulum (ER) stress in a corneal endothelium in a subject, comprising the step of administering an effective amount of a transforming growth factor-β (TGF-β) signal inhibitor to the subject.

2 . The method of claim 1 , wherein the disease, disorder or condition is associated with mitochondrial failure.

3 . The method of claim 1 , wherein the disease, disorder or condition is associated with apoptosis due to mitochondrial failure.

4 . The method of claim 1 , wherein the disease, disorder or condition is related to Fuchs' endothelial corneal dystrophy.

5 . The method of claim 1 , wherein the therapeutic or prophylactic drug suppresses the disease, disorder or condition comprising a disorder of a corneal endothelial cell in Fuchs' endothelial corneal dystrophy.

6 . The method of claim 1 , wherein the therapeutic or prophylactic drug suppresses at least one of the disease, disorder or condition selected from the group consisting of decreased corneal endothelial density, guttae formation, hypertrophy of the Descemet's membrane, hypertrophy of a cornea, corneal epithelial disorder, turbidity in corneal stroma, photophobia, blurred vision, visual impairment, ophthalmalgia, epiphora, hyperemia, pain, bullous keratopathy, eye discomfort, diminished contrast, glare, and edema of the corneal stroma.

7 . The method of claim 1 , wherein the TGF-β signal inhibitor comprises at least one of 4-[4-(1,3-benzodioxole-5-yl)-5-(2-pyridinyl)-1H-imidazole-2-yl]benzamide, BMP-7, an anti-TGF-β antibody, an anti-TGF-β receptor antibody, a siRNA of TGF-β, a siRNA of a TGF-β receptor, a shRNA of TGF-β, a shRNA of a TGF-β receptor, an aptamer of TGF-β, an aptamer of a TGF-β receptor, an antisense oligonucleotide of TGF-β, 6,7-dimethoxy-2-((2E)-3-(1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyr idine-3-yl-prop-2-enoyl))-1,2,3,4-tetrahydroisoquinolone, 2-(3-(6-methylpyridine-2-yl)-1H-pyrazole-4-yl)-1,5-naphthyr idine, 6-(4-(piperidine-1-yl) ethoxy)phenyl)-3-(pyridine-4-yl)pyrazolo[1,5-a]pyrimidine, 2-(5-chloro-2-fluorophenyl)-4-[(4-pyridinyl)amino]pteridine 4-[3-(2-pyridinyl)-1H-pyrazole-4-yl]-quinoline, A-83-01 (3-(6-methyl-2-pyridinyl)-N-phenyl-4-(4-quinolinyl)-1H-pyrazol e-1-carbothioamide), a pharmaceutical acceptable salt or solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

8 . The method of claim 1 , wherein the TGF-β signal inhibitor comprises 4-[4-(1,3-benzodioxole-5-yl)-5-(2-pyridinyl)-1H-imidazole-2-yl]benzamide or a pharmaceutically acceptable salt thereof.

9 . The method of claim 1 , further comprising administering an effective amount of a therapeutic agent for mitochondrial failure induced by ER stress to the subject.

10 . The method of claim 9 , wherein the therapeutic agent for mitochondrial failure induced by ER stress is selected from the group consisting of BiP inducer X (BIX), 4-phenyl butyric acid (PBA), trimethylamine N-oxide (TMAO), tauroursodeoxycholic acid (TUDCA), and teprenone.

11 . The method of claim 1 , wherein the corneal endothelium is from a primate.

12 . The method of claim 1 , wherein the corneal endothelium is from a human.

13 . The method of claim 1 , wherein the TGF-β signal inhibitor is administered in combination with an additional pharmaceutical ingredient.

14 . The method of claim 1 , wherein the TGF-β signal inhibitor is administered as eye drops.

Assignees

• Kyoto Prefectural Public Univ Corp
• The Doshisha
• Senju Pharma Co

Inventors

• Koizumi Noriko
• Okumura Naoki
• Kinoshita Shigeru

Classifications

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07K16/22

  against growth factors {; against growth regulators} · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K38/005

  Enzyme inhibitors (protease inhibitors A61K38/55) · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title