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Dual-action inhbitors and methods of using same

a dual-action, inhbitor technology, applied in the field of mammals' compounds, compositions, methods of treating diseases and conditions, can solve problems such as eye damage, and achieve the effect of modulating the action

Inactive Publication Date: 2012-05-31
AERIE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes compounds that can treat various diseases and conditions by inhibiting a kinase and monoamine transport. The compounds can be used alone or in combination with other therapeutic agents such as beta blockers, alpha-agonists, carbonic anhydrase inhibitors, prostaglandin-like compounds, miotic or cholinergic agents, and epinephrine compounds. The technical effects of the patent include providing new compounds for the treatment of various diseases and conditions, as well as methods for reducing intraocular pressure, treating cardiac indications, respiratory disorders, renal diseases, and inflammatory diseases, among others.

Problems solved by technology

Damage or death of the primary light-sensing cells, the photoreceptors, results in devastating effects on vision.

Method used

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  • Dual-action inhbitors and methods of using same
  • Dual-action inhbitors and methods of using same
  • Dual-action inhbitors and methods of using same

Examples

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examples

[0170]These examples are intended to illustrate the invention to those skilled in the art and should not be interpreted as limiting the scope of the invention set forth in the claims.

Reference Example One

The Cell-Based Porcine Trabecular Meshwork (PTM) Assay

[0171]The anterior section of porcine eyes was harvested within 4 hours post-mortem. The iris and ciliary body were removed and trabecular meshwork cells were harvested by blunt dissection. Finely minced trabecular meshwork tissue was plated into collagen-coated 6-well plates in Medium-199 containing 20% fetal bovine serum (FBS). After two passages at confluence, cells were transferred to low-glucose DMEM containing 10% FBS. Cells were used between passage 3 and passage 8.

[0172]Cells were plated into fibronectin-coated, glass multiwell plates the day before compounds were tested under standard culture conditions. Compounds were added to cells in the presence of 1% FBS-containing DMEM and 1% DMSO. When compounds were incubated wit...

reference example two

NET / SERT Assay

[0174]Norepinephrine Transporter (NET) Membrane Radioligand Binding Assays. Total cell membranes were prepared from MDCK cells expressing the recombinant human norepinehrine transporter (hNET) grown to confluence in 150 mm tissue culture dishes. Cells were scraped into standard medium and pelleted at 1600 g. The medium was discarded and the pellet resuspended in 5 ml per plate of ice-cold binding buffer (100 mM NaCl, 50 mM Tris, pH 7.4 at room temperature) by trituration, and the cells were repelleted at 20,000 g. Supernatant was discarded and cells were resuspended in binding buffer (50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 μM leupeptin, 10 μM PMSF) and homogenized with a polytron (Brinkman) at 25,000 revs / min for 5 s. Centrifugation, resuspension and homogenization were repeated and a sample of suspension was used for Bradford protein determination (BioRad). Samples of membrane suspensions were frozen at −80° C. prior to use. Typical yields were about 100 μg membrane p...

reference example three

Pharmacological Activity for Glaucoma Assay

[0176]Pharmacological activity for glaucoma can be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein by reference: C. Liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, “Derivatives of 17-phenyl-18,19,20-trinorprostaglandin F2alpha Isopropyl Ester: Potential Anti-glaucoma Agents”, Journal of Medicinal Chemistry 1995, 38 (2): 289-304.

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Abstract

Provided are compounds, compositions, and methods for treating diseases and conditions wherein an inhibitor of a kinase, such as rho kinase (ROCK), and an inhibitor of one or more of the monoamine transporters, such as NET or SERT, act in concert to improve the condition.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 61 / 174,672, filed May 1, 2009, and incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]This invention relates to compounds, compositions, and methods for treating diseases and conditions in mammals.BACKGROUND OF THE INVENTION[0003]A variety of hormones, neurotransmitters and biologically active substances control, regulate or adjust the functions of living bodies via specific receptors located in cell membranes. Many of these receptors mediate the transmission of intracellular signals by activating guanine nucleotide-binding proteins (G proteins) to which the receptor is coupled. Such receptors are generically referred to as G-protein coupled receptors (GPCRs) and include, among others, α-adrenergic receptors, β-adrenergic receptors, opioid receptors, cannabinoid receptors and prostaglandin receptors. The biological effects of activating these re...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4725C07D217/02A61K31/472C07D409/12C07D417/12C07D409/14C07C237/42A61K31/167A61K31/235C07C69/74A61K31/215C07D333/38A61K31/381A61K31/496A61K31/551C07D237/28A61K31/502C07D231/56A61K31/416C07D317/60A61P27/02A61P27/06A61P9/00A61P11/00A61P13/12A61P29/00A61K31/36C12N9/99C07D401/12
CPCC07C237/20C07C2101/08C07C2101/14C07D217/00C07D333/40C07D409/12C07D417/12C07C237/42C07D401/12C07C2601/08C07C2601/14C07D217/04C07D217/02C07D217/22C07D217/24C07D405/12C07D413/12C07D333/38A61P1/00A61P1/04A61P1/16A61P1/18A61P11/00A61P11/02A61P13/10A61P13/12A61P15/18A61P17/00A61P17/14A61P19/02A61P19/08A61P27/00A61P27/02A61P27/04A61P27/06A61P29/00A61P3/04A61P35/00A61P43/00A61P9/00A61P9/10A61P9/12
Inventor DELONG, MITCHELL A.STURDIVANT, JILL MARIEROYALTY, SUSAN M.HEINTZELMAN, GEOFFREY RICHARDYINGLING, JEFFREY D.KOPCZYNSKI, CASEY
Owner AERIE PHARMA
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