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Ocular compositions that increases the activity of gelatinase a in ocular cells

a technology of ocular cells and compositions, which is applied in the field of ocular compositions that increase the activity of gelatinase a in ocular cells, can solve the problems of decreased iop, increased degradation of ecm, and subsequent increase in aqueous outflow, so as to increase the expression or enzymatic activity, increase the aqueous outflow, and increase the effect of ecm degradation

Inactive Publication Date: 2006-06-08
PFEFFER BRUCE ALAN +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0029] Small organic molecules in accordance with the present invention are therapeutically useful in the treatment of diseases termed primary open angle glaucoma by having a pharmacological effect on cells and tissue. The subject small organic molecules increase the expression or enzymatic activity of MT-MMP, or a similar enzyme expressed in the TM, that activates GelA. Activation of GelA leads to increased degradation of ECM and a subsequent increase in aqueous outflow with a resultant decrease in IOP.
[0032] Accordingly, it is an object of the present invention to provide small organic molecules effective in the treatment of primary open angle glaucoma.
[0034] Another object of the present invention is to provide a method of effectively treating primary open angle glaucoma.
[0037] Still another object of the present invention is to provide a method of manufacturing small organic molecules effective in the treatment of primary open angle glaucoma.

Problems solved by technology

Activation of GelA leads to increased degradation of ECM and a subsequent increase in aqueous outflow with a resultant decrease in IOP.

Method used

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  • Ocular compositions that increases the activity of gelatinase a in ocular cells
  • Ocular compositions that increases the activity of gelatinase a in ocular cells
  • Ocular compositions that increases the activity of gelatinase a in ocular cells

Examples

Experimental program
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Effect test

example 1

Small Molecules that Increase Expression or Activity of a Cell-Associated Component with Gelatinase Activity, Detected Using a Cell-Based Screening Assay that Measures Hydrolysis of a Thiopeptolide Substrate

[0091] A. Thiopeptolide Assay Used to Detect Cell-Associated Gelatinase Activity Ascribed to MT-MMP:

[0092] Rhesus monkey TM cells are cultured and maintained for at least two weeks in 96-well microtiter plates in a growth medium such as Dulbecco's Modified Eagles' Medium (DMEM) plus 15 percent (v / v) fetal bovine serum (FBS)containing 1% bovine calf serum or a medium more suitable for endothelial cells due to its lower serum content such as MCDB 131 supplemented with endothelial cell growth supplement, 1% or less FBS or bovine calf serum and defined supplements as described by Knedler and Ham, In Vitro Cellular and Dev. Biol. 23:481 (1987). Two days before molecule testing, the medium is replace by a defined, serum-free medium such as Minimum Essential Medium (MEM) containing de...

example 2

Small Molecules that Have a Synergistic Effect when Used in Combination, with Each Other or with the Lectin Concanavalin A, on the Increased Expression or Activity of a Cell-Associated Component with Gelatinase Activity, Detected Using a Cell-Based Screening Assay that Measures Hydrolysis of a Thiopeptolide Substrate

[0107] Concanavalin A (Con A) binds to mannose groups on cell membrane gycoproteins. Because of its tetravalent nature, Con A binding leads to oligomerization of these “receptors,” possibly in the form of heterogeneous aggregates. Con A stimulation elicits increased expression of MT-MMP with concomitant ability to activate proGel A. The response, as measured by the magnitude of zymographic bands and by thiopeptolide assay, is dose-dependent. Thus the effects of co-activation using a submaximal dose of Con A plus treatment with a small molecule that may or may not be active by itself, are measured in the subject activation assay.

[0108] A. Co-Activation Assay Used to Det...

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Abstract

Compositions capable of effecting a “pharmacological trabeculocanalotomy” in an eye by means of reducing juxtacanalicular meshwork as a barrier to outflow of aqueous. The small organic molecules increase Gelatinase A activity in ocular cells by increasing cell membrane expression of membrane-type matrix metalloproteinases (MT-MMPs) to increase aqueous outflow as a treatment for primary open angle glaucoma.

Description

CROSS REFERENCE [0001] This application is a divisional of 10 / 260,448 filed Sep. 27, 2002, which is incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention relates generally to compositions capable of effecting a “pharmacologic trabeculocanalotomy” in an eye by means of reducing juxtacanalicular meshwork as a barrier to outflow of aqueous. More specifically, the present invention relates to small organic molecules that increase Gelatinase A activity in ocular cells by increasing cell membrane expression of membrane-type matrix metalloproteinases (MT-MMPs) to increase aqueous outflow as a treatment for primary open angle glaucoma. The present invention likewise includes methods of manufacturing and using such small organic molecules in the treatment of primary open angle glaucoma. BACKGROUND OF THE INVENTION [0003] The extracellular matrix (ECM) of an eye is an association of specialized proteins, glycoproteins, and proteoglycans, that subserve and impar...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/47A61K31/445A61K31/426A61K31/405A61K31/381A61K31/4172A61K31/325A61K31/4453C07C275/10C07C281/18C07D223/26C07D279/22C07D295/205
CPCC07C275/10C07C281/18C07D295/205C07D279/22C07D223/26A61P27/02A61P27/06A61P43/00A61K31/4453A61K31/155
Inventor PFEFFER, BRUCE ALANFLICK, ROSEMARIE BETHSHAMS, NAVEED BIN KAMALBARTELS, STEPHEN PAUL
Owner PFEFFER BRUCE ALAN