Drug for treating corneal endothelium by promoting cell proliferation or inhibiting cell damage

Patent metadata

Field	Value
Publication number	US-2016331736-A1
Application number	US-201415034710-A
Country	US
Kind code	A1
Filing date	Nov 13, 2014
Priority date	Nov 14, 2013
Publication date	Nov 17, 2016
Grant date	—

Abstract

Provided is an agent for treating or preventing a corneal endothelial disorder wherein cell proliferation is required. More specifically, provided is an agent for treating or preventing a corneal endothelial disorder, wherein cell proliferation is required, said agent comprising a p38MAP kinase inhibitor. In a preferred embodiment, the corneal endothelial disorder is a wound. In a preferred embodiment, the p38MAP kinase inhibitor is soluble in water. The p38MAP kinase inhibitor may comprise 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazole-5-yl]pyridine (SB203580) or a salt thereof.

First claim

1 . A therapeutic or prophylactic drug for a corneal endothelial disease, disorder or condition requiring cell proliferation, suppression of a cellular disorder or suppression of cellular senescence, comprising a p38 MAP kinase inhibitor.

2 . The therapeutic or prophylactic drug of claim 1 , wherein the corneal endothelial disorder is at least one selected from the group consisting of Fuchs' endothelial corneal dystrophy, sustained decrease in corneal endothelial density after corneal transplantation, trauma, ophthalmic surgery, aging, and disorder associated with corneal endotheliitis.

3 . The therapeutic or prophylactic drug of claim 1 , wherein the p38 MAP kinase inhibitor is water-soluble.

4 . The therapeutic or prophylactic drug of claim 1 , wherein the p38 MAP kinase inhibitor comprises at least one selected from the group consisting of 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB-202190), trans-4-[4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imidazole-1-yl]cyclohexanol(SB-239063), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB-203580), 4-(4-fluorophenyl)-5-(2-methoxypyrimidine-4-yl)-1-(piperidine-4-yl)imidazole (SB-242235), 4-(4-fluorophenyl)-2-(4-hydroxy-1-butynyl)-1-(3-phenylpropyl)-5-(4-pyridyl)imidazole (RWJ-67657), 4-(4-fluorophenyl)-1-(piperidine-4-yl)-5-(4-pyridyl)imidazole (HEP-689), (S)-2-(2-amino-3-phenylpropylamino)-1-methyl-5-(2-naphthyl)-4-(4-pyridyl)pyrimidine-6-one (AMG-548), 2-chloro-4-(4-fluoro-2-methylanilino)-2′-methylbenzophenone (EO-1606), 3-(4-chlorophenyl)-5-(1-hydroxyacetylpiperidine-4-yl)-4-(pyrimidine-4-yl)pyrazole (SD-06), 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)pyrimido[3,4-b]pyridazine-6-one (VX-745), 4-acetylamino-N-tert-butylbenzamide (CPI-1189), N-[3-tert-butyl-1-(4-methylphenyl)pyrazole-5-yl)-N′-[4-(2-morpholinoethoxy)-1-naphthyl]urea (Doramapimod (BIRB796)), 2-benzamide-4-[2-ethyl-4-(3-methylphenyl)thiazole-5-yl]pyridine (TAK-715), Talmapimod (SCIO-469), 1-(carbamoyl-6-(2,4-difluorophenyl)pyridine-2-yl)-1-(2,6-difluorophenyl) urea (VX-702; 2-(2,4-difluorophenyl)-6-(1-(2,6-difluorophenyl)ureido)nicotinamide), dilmapimod (GSK-681323), 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo(1,2-f)(1,2,4)triazine-6-carboxamide (PS-540446), anti-FGF-7 antibody (SC-80036), AVE-9940, [5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-yl][3-(3-amino-2-hydroxypropoxy)phenyl]methanone (RO-320-1195), 1-(1,3-dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-[2-phenoxypyrimidine-4-yl]imidazole (SB-281832), 2-[5-({4-[(4-fluorophenyl)methyl]piperidine-1-yl}carbonyl)-6-methoxy-1-methyl-1H-indole-3-yl]-N,N′-dimethyl-2-oxoacetamide (SCIO-323), 2-(5-tert-butyl-2-m-tolyl-2H-pyrazole-3-yl)-2-hydroxyimide-N-[4-(2-morpholine-4-yl-ethoxy)-naphthalene-1-yl]-acetamide (KC-706), N,N′-bis[3,5-bis[1-(2-amidinohydrazono)ethyl]phenyl]decandiamide, N,N′-bis[3,5-bis[1-[2-(aminoiminomethyl)hydrazono]ethyl]phenyl]decandiamide (Semapimod), 3-(3-bromo-4-((2,4-difluorobenzyl)oxy)-6-methyl-2-oxopyridine-1(2H)-yl)-N,4-dimethylbenzamide (PH-797804), and 5-(2-(tert-butyl)-5-(4-fluorophenyl)-1H-imidazole-4-yl)-3-neopentyl-3H-imidazo[4,5-b]pyridine-2-amine (LY2228820).

5 . The therapeutic or prophylactic drug of claim 1 , wherein the p38 MAP kinase inhibitor is 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazole-5-yl]pyridine (SB203580) or a salt thereof.

6 . The therapeutic or prophylactic drug of claim 1 , wherein the p38 MAP kinase inhibitor comprises 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazole-5-yl]pyridine (SB203580) hydrochloride.

7 . A p38 MAP kinase inhibiting substance for treatment or prevention of a corneal endothelial disorder requiring cell proliferation.

8 . A method of treating or preventing a corneal endothelial disorder requiring cell proliferation, comprising the step of administering an effective amount of a p38 MAP kinase inhibitor to a subject in need thereof.

Assignees

• The Doshisha

Inventors

• Koizumi Noriko
• Okumura Naoki
• Kinoshita Shigeru

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/4418

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title