Method for enhancing outflow of aqueous humor in treatment of glaucoma

• US 20020016346A1
• Filed: 02/16/2001
• Published: 02/07/2002
• Est. Priority Date: 12/09/1994
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Brandt, James D., OʼDonnell, Martha E., Curry, Fitz-Roy E.
• Granted Patent: US 6,576,219 B2
• Time in Patent Office: Days
• US Class Current: 514/347
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/402 1-aryl substituted, e.g. piretanide
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof

Abstract

Elevated intra-ocular pressure is reduced by administration directly to the eye of compounds that inhibit function of a Na⁺—K⁺—2Cl⁻² cotransporter mechanism discovered in trabecular meshwork cells of mammalian eyes. These compounds are useful in treatment of diseases of the eye associated with elevated intra-ocular pressure, such as ocular hypertension and glaucoma. A screening method is provided to discover additional compounds with utility for lowering intra-ocular pressure by substantially inhibiting the Na⁺—K⁺—Cl⁻² cotransporter mechanism in trabecular meshwork cells.

Claims

1. A method for screening compounds for utility in lowering intra-ocular pressure comprising:

(a) Determining the IC50 concentration of compounds in the cortical thick ascending limb of the loop of Henle;

(b) Determining the inhibition of Na⁺—

K⁺—

2Cl⁻

cotransport in mammalian trabecular meshwork cells;

(c) Selecting compounds with an IC50 at or below 0.30 μ

M and an inhibition of Na⁺13 K⁺—

2Cl⁻

cotransport of at least 50%.

2. The method of claim I wherein the cortical thick ascending limb is in rabbit and the trabecular meshwork cells are bovine or human.

3. A method for screening compounds for utility in lowering intra-ocular pressure comprising selecting compounds that substantially inhibit a Na⁺—

K⁺2Cl⁻

cotransporter mechanism.

4. The method of claim 3 wherein the Na⁺—

K⁺—

2Cl⁻

cotransporter mechanism is in mammalian trabecular meshwork cells and the compound selected has an IC50 of about 0.30 μ

M or less.

5. The method of claim 4 wherein the trabecular meshwork cells are human.

6. The method of claim 5 wherein the trebecular meshwork cells are bovine.

7. The method of claim 6 wherein the compound selected further has a coefficient of lipophilicty (log P′

) of at least 0.005.

8. The method of claim 7 wherein the compound selected further has a coefficient of lipophilicity (log P′

) of at least 0.01.