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3-Pyridinecarboxamide derivatives as HDL-cholesterol raising agents

a technology of hdl-cholesterol and derivatives, which is applied in the direction of biocide, drug composition, metabolic disorders, etc., can solve the problems of not being able to achieve wholly satisfactory hdl-elevating therapies, reducing compliance, and significantly elevating plasma hdl levels, so as to achieve the effect of potent hdl-cholesterol raising agents and treatment and/or prophylaxis of diseases

Inactive Publication Date: 2008-04-10
F HOFFMANN LA ROCHE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] An object of the present invention is therefore to provide compounds which are potent HDL-cholesterol raising agents. It has been found that compounds of formula I show such a potential.
[0010] Further, the present invention relates to pharmaceutical compositions comprising a

Problems solved by technology

No wholly satisfactory HDL-elevating therapies exist.
Niacin can significantly increase HDL, but has serious toleration issues which reduce compliance.
As a result, there is a significant unmet medical need for a well tolerated agent which can significantly elevate plasma HDL levels.

Method used

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  • 3-Pyridinecarboxamide derivatives as HDL-cholesterol raising agents
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  • 3-Pyridinecarboxamide derivatives as HDL-cholesterol raising agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effects on Plasma Lipid Levels in Lean, Chow Fed Rats

[0537] Effects of compounds of formula I on plasma lipid levels were determined in lean, chow-fed male Sprague-Dawley rats with compounds administered by p.o. gavage. After one week of acclimation, blood samples were collected from 4 hour-fasted animals for plasma lipid determination. Animals were then assigned to treatment groups based on HDL-cholesterol levels. Compounds of formula I were administered by gavage, once daily for five days. Control animals received vehicle alone. Blood was collected on day five from 4 hour-fasted rats, 2 hours after a final treatment, for plasma lipid analysis. Total cholesterol, HDL-cholesterol, and triglycerides were determined by measuring total cholesterol, HDL-cholesterol, and triglyceride using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-C was also quantified using size exclusion chromatography on superpose-6 column using a SMART system (Pharmacia). Lipoprot...

example 2

Effects on Plasma Lipid Levels in Obese, High Fat Diet Fed Rats

[0538] Efficacy of compounds in modulating plasma lipid levels was determined also in obese male Sprague Dawley rats after 28-29 days administration of compounds. Male Sprague-Dawley rats of 10 weeks of age were fed a high fat diet during 3 weeks. Obese rats were distributed in groups according to homogeneous BW and FI evaluated a week before the start of the treatment. Treatment was administered as food-Admix. On day 29, blood was taken in the morning under slight anesthesia (retro-orbital method) in post-prandial conditions i.e. 4 h after food was removed. Plasma was separated from blood by low speed centrifugation and selected organs were taken (e.g liver, fat). Total cholesterol, HDL-cholesterol, and triglycerides were determined by measuring total cholesterol, HDL-cholesterol and triglyceride using calorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-C was also quantified using size exclusi...

example 3

Effects on Plasma Lipid Levels in Hamsters

[0539] Efficacy of compounds in modulating plasma lipid levels was determined in hamsters after 5 days of daily administration of compounds. Male hamsters of 6-8 weeks of age were used in the studies. After one week of acclimation, blood samples were collected from 4 hour-fasted animals for plasma lipid determination. Animals were then assigned to treatment groups based on HDL-cholesterol levels. Compounds were administered by gavage, once daily for five days. Control animals received vehicle alone. Blood was collected on day five from 4 hour-fasted hamsters, 2 hours after a final treatment, for plasma lipid analysis. Total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides were determined using calorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-cholesterol, LDL-cholesterol, and VLDL-cholesterol levels were also quantified using size exclusion chromatography on superpose-6 column using a SMART system...

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Abstract

The present invention relates to a method of raising HDL cholesterol comprising administering to a patient in need thereof a compound of the formula wherein A, G, R1 to R8 and R17 are as defined in the description.

Description

PRIORITY TO RELATED APPLICATION(S) [0001] This application claims the benefit of European Patent Application No. 06121755.0, filed Oct. 4, 2006, which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] The present invention is concerned with the use of 3-pyridinecarboxamide or 2-pyrazinecarboxamide derivatives as HDL-cholesterol raising agents. [0003] Atherosclerosis and its associated coronary heart disease is the leading cause of death in the industrialized world. Risk for development of coronary heart disease has been shown to be strongly correlated with certain plasma lipid levels. Lipids are transported in the blood by lipoproteins. The general structure of lipoproteins is a core of neutral lipids (triglyceride and cholesterol ester) and an envelope of polar lipids (phospholipids and non esterified cholesterol). There are 3 different classes of plasma lipoproteins with different core lipid content: the low density lipoprotein (LDL) which is ...

Claims

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Application Information

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IPC IPC(8): A61K31/4965A61K31/4406A61P9/00
CPCC07D213/74C07D241/24C07D213/82A61P3/10A61P3/04A61P3/06A61P43/00A61P9/00A61P9/10A61P9/12A61K31/44A61K31/465
Inventor ANDJELKOVIC, MIRJANABENARDEAU, AGNESCHAPUT, EVELYNEHEBEISEN, PAULNETTEKOVEN, MATTHIASSANDER, ULRIKE OBSTPANOUSIS, CONSTANTINOS G.ROEVER, STEPHAN
Owner F HOFFMANN LA ROCHE INC
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