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Treatment of cardiac conditions

A technology for heart disease and ischemic heart disease, applied in the field of compound compound) as an inotropic agent for the treatment of cardiac dysfunction, which can solve the problem of unclear mechanism of action of gastric oxyntomodulin and inability to activate glucagon receptor And other issues

Inactive Publication Date: 2013-01-23
ZEALAND PHARM AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, GLP-1 does not activate the glucagon receptor
Mechanism of action of oxyntomodulin is unclear

Method used

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  • Treatment of cardiac conditions
  • Treatment of cardiac conditions
  • Treatment of cardiac conditions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1086] Example 1. Evaluation of inotropic effects in a working heart model

[1087] The inotropic compound glucagon and the glucagon-GLP-1 dual agonist (compound 12, with the sequence HSQGTFTSDYSKYLDRARADDFVAWLKST) were evaluated in isolated working hearts from control and insulin-resistant JCR:LA-cp rats. Role of cardiac function, metabolism and energy status (Lopaschuk, GD and Barr, RL. Measurements of fatty acid and carbohydrate metabolism in the isolated working rat heart. Molecular and Cellular Biochemistry. 1997; 172: 137-147). Isolated working hearts were perfused aerobically with Krebs-Henseleit solution (11 mM glucose, 2000 μU / ml insulin, 1.25 mM free Ca2+, 0.8 mM palmitate, and 3% BSA), and gradually added to the perfusion buffer during the perfusion. Increasing concentrations (10, 50 and 100 mM) of glucagon or compound 12. After perfusion, high-energy phosphate nucleotide concentrations were measured by high-performance liquid chromatography (HPLC) (Ally, A and Par...

Embodiment 2

[1089] Example 2. Determination of Potency on GLP-1 and Glucagon Receptors

[1090] HEK293 cells expressing human glucagon receptor or human GlP-1R (see above for details) were seeded at 40,000 cells / well into 96-well microtiter plates coated with 0.01% poly-L-lysine , and grown in cultures in 100 μl of growth medium for 1 day. On the day of analysis, the growth medium was discarded and the cells were washed once with 200 μl Tyrode's buffer. Cells were incubated for 15 minutes at 37°C in 100 µl of Tyrode's buffer containing increasing concentrations of the test peptide, 100 µM IBMX and 6 mM glucose. The reaction was stopped by adding 25 μl of 0.5M HCl and incubated on ice for 60 minutes. Using from Perkin-Elmer The cAMP kit assesses cAMP levels. Estimation of EC by computer-aided curve fitting 50 value.

[1091] Table 1 shows sample compounds EC 50 value result.

[1092]

[1093]

[1094] Brackets () indicate intramolecular lactam rings.

Embodiment 3

[1095] Example 3. Evaluation of inotropic effects in anesthetized rats

[1096] The effects of inotropic Compound 1 and a glucagon-GLP-1 dual agonist (Compound 12) on cardiac function and heart rate were tested in anesthetized male Sprague-Dawley rats (Taconic) weighing approximately 300-400 g.

[1097] Rats were exposed to 1:2 N 2 O:O 2 in 5% isoflurane until anesthesia is confirmed. Body temperature was kept constant (37.5±0.5°C), animals were artificially ventilated by endotracheal intubation, and anesthesia was maintained.

[1098] The left femoral vein was catheterized for drug administration, and a pressure-volume catheter was inserted through the right carotid artery into the left ventricle. After installing the instrument, use pure O during the experiment 2 Delivery of isoflurane. After 20 minutes of stabilization, baseline data were recorded for 15 minutes while vehicle was being infused (at 7 L / min). Subsequently, the compound is infused. A 2.5 nmol / kg / min dos...

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Abstract

The invention relates to the treatment of cardiac dysfunction. In particular, certain compounds, believed to be glucagon-GLP-1 dual agonist compounds, exert a positive inotropic effect while preserving the energy balance of the heart, and so may be superior to known inotropic agents such as dobutamine, norepinephrine and glucagon.

Description

technical field [0001] The present invention relates to the use of compounds, typically glucagon-GLP-1 dual agonist compounds, as inotropic agents for the treatment of cardiac dysfunction. Background technique [0002] Positive inotropic agents are used to improve hemodynamic parameters and thus reduce symptoms and protect end organs in patients with myocardial infarction, heart failure or cardiogenic shock. The heart requires large amounts of chemical energy to support contraction and relaxation. Thus, by increasing the work of the heart, inotropes also increase the energy demands of the heart. However, a failing or diseased heart is often energy starved (Ingwall, JS and Weiss, RG. Circ Res. 2004; 95: 135-145), so the use of inotropes can lead to energy depletion and ultimately increased mortality (Hamad , E et al. American Journal of Cardiovascular Drugs. 2007; 7: 235-248; White, CM. J Clin Pharmacol. 1999; 39: 442-447). [0003] Preproglucagon is a 158 amino acid precu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/26A61P9/04
CPCA61K38/26C07K14/4705C07K14/605A61P9/04A61P9/10A61K9/0021
Inventor 约根·索贝格·彼得森安妮·路易斯·舍尔比马里耶·斯科夫高亨利克·迪尤隆德·彼得森莱娜·阿克塞尔森迪特·里贝尔埃迪·迈尔里·舒尔茨·汉森克尔德·福斯格劳比亚内·杜·拉森
Owner ZEALAND PHARM AS
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