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Compounds and methods of treating hypertension

a hypertension and compound technology, applied in the field of compound and method of treating hypertension, can solve the problems of increasing urine sodium content and/or urine volume, increasing renal blood flow, and increasing urine sodium content, so as to increase renal blood flow, reduce sodium reabsorption, and increase renal blood flow

Inactive Publication Date: 2014-10-09
MEDIVATION TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods for increasing renal blood flow, decreasing sodium reabsorption, reducing edema, and reducing elevated blood urea nitrogen to creatinine ratio in individuals with various conditions such as congestive heart failure and renal insufficiency. The methods involve administering specific compounds or salts thereof.

Problems solved by technology

In one embodiment, the method results in increase in renal blood flow.
In another embodiment, the method results in decrease in sodium reabsorption.
In another embodiment, the method results in increase in urine sodium content and / or increase in urine volume.

Method used

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  • Compounds and methods of treating hypertension
  • Compounds and methods of treating hypertension
  • Compounds and methods of treating hypertension

Examples

Experimental program
Comparison scheme
Effect test

example b1

Determination of the Ability of Compounds of the Invention to Bind an Adrenergic Receptor

Adrenergic α2B

[0551]To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α2B receptor expressed in Chinese hamster ovary (CHO) K1 cells (Uhlen, S. et al, Eur. J. Pharmacol. 343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA) was used. Compounds of the invention were incubated with 2.5 nM [3H]Rauwolscine for 60 min at 25° C. Non-specific binding was estimated in the presence of 10 μM Prazosin. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Rauwolscine specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific ...

example b2

Functional Activity on Recombinant Adrenergic α1B, Adrenergic α2A Adrenergic α2B and Adrenergic α1D Receptors Using Aequorin and GTPγS Functional Assays

[0555]To study the functional activity of compounds of the invention on the human recombinant adrenergic α2B, adrenergic α2A, adrenergic α1B or adrenergic α1D with Aequorin functional assays and on the human recombinant adrenergic α2B receptor with GTPγS assay, CHO-K1 cell lines expressing adrenergic α2B, adrenergic α2A, adrenergic α1B or adrenergic α1D recombinant receptor, mitochondrial apoaequorin and Gα16 are used for the Aequorin assay. CHO-K1 cell line expressing the recombinant α2B receptor is amplified to prepare membranes used for the GTPγS assay.

[0556]The following reference agonists are used as both the reference ligand in agonist mode and as the agonist that needs to be inhibited in antagonist mode.

α2BAssayα1B (aeq)α1D (aeq)α2A (aeq)α2B (aeq)(GTPgS)AgonistCirazolineCirazolineUK 14304Oxyme-Guanfacineligandtazoline

[0557]Aeq...

example b3

Cell Culture and Cell Viability Assay

[0568]SH-SY5Y cells cultured in DMEM / F12 media supplemented with 10% FBS were seeded in 96-well microplates at 150,000 cells / cm2. After 24 h, cells were depleted from FBS and kept in culture for 24 h before the experiment. A stock solution was prepared by dissolving the calcium ionophore 4-Br-A23187 (Calbiochem Cat. No 100107) in DMSO at 25 mM. Cells were then treated with 4-Br-A23187 (2 μM), hydrogen peroxide (300 μM) or the mitochondrial toxin rotenone (25 μM) in the presence of vehicle or Compound of the Invention for 24 h. Cell death was determined by measurements of LDH release according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany). Cell viability was determined by measuring the capacity of cells to metabolize MTS tetrazolium (MTS) according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany) and MTS reduction was assessed by the CellTiter 96® AQueous One Solution Cell Proliferation assay (Promega Corporation...

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Abstract

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. The compounds may bind to and are adrenergic receptor α2B antagonists. The compounds may also bind to and antagonize adrenergic receptor α2B. The compounds may find use in therapy, e.g., to (i) reduce blood pressure and / or (ii) promote renal blood flow and / or (iii) decrease or inhibit sodium reabsorption. The compounds may also be used to treat diseases or conditions that are, or are expected to be, responsive to a decrease in blood pressure. Use of the compounds to treat cardiovascular and renal disorders is particularly described.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Application No. 61 / 444,616 filed Feb. 18, 2011, U.S. Provisional Patent Application No. 61 / 444,553 filed Feb. 18, 2011, and U.S. Provisional Patent Application No. 61 / 444,569 filed Feb. 18, 2011, the disclosures of each of which are incorporated herein by reference in their entireties.BACKGROUND OF THE INVENTION[0002]Hypertension is a serious condition that can damage vital organs, such as the heart and kidneys, and other parts of the body, such as the central nervous system. Individuals who have hypertension may have, or be at risk of developing, dangerous diseases such as coronary heart disease and kidney failure. Hypertension, which is the leading modifiable risk factor for cardiovascular disease mortality, causes more than 7 million deaths every year worldwide.[0003]Hypertension is the most common chronic medical condition in developed countries as well as the most common ind...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D513/16C07D498/16C07D471/04C07D471/08C07D487/08C07D487/04C07D471/14
CPCC07D513/16C07D487/04C07D498/16C07D471/14C07D471/08C07D487/08C07D471/04A61K31/437A61K31/4375A61K31/46A61K31/4985A61K31/506A61K31/519A61K31/5383A61K31/542A61K31/55A61K31/553C07D451/00C07D471/16C07D471/22C07D487/16C07D498/22
Inventor PROTTER, ANDREW ASHERCHAKRAVARTY, SARVAJIT
Owner MEDIVATION TECH INC
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