Activators of peroxisome proliferator-activated receptor

Inactive Publication Date: 2005-11-10
KOWA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] Accordingly, an object of the present invention is to provide PPAR activators with reduced adverse effects.

Problems solved by technology

Further, symptoms such as hyperinsulinemia, hypo HDL cholesterolemia, hypertension, and obesity most frequently occur with hyperlipidemia and diabetes, which raises clinical problems.
However, PPAR agonists are reported to generally have adverse effects such as liver function failure, and accordingly, a patient with liver function failure contraindicates the use of troglitazone, one of the PPARγ agonists (Reference: Rinsho Iyaku, 14, 461-466 (1998)), and the sale of said drug was currently discontinued.

Method used

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  • Activators of peroxisome proliferator-activated receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

Expression of PPARα and PPARγ mRNA in Human Cell Line

[0024] Caco-2 cells (derived from colon cancer) as a human cell line were cultured at 37° C. in RPMI-1640 medium containing 10% fetal calf serum in the presence of 5% CO2. The medium was then replaced with serum-free RPMI-1640 medium and the cells were cultured for 48 hours. In order to examine the effect of NIK-333, a solution of NIK-333 in ethanol was added at a final concentration of 10 μM. At 0, 0.5, 1, 2 and 5 hours after the addition, RNA was extracted to observe mRNA for PPARα, PPARγ 1 and PPARγ 2 by the RT-PCR method.

[0025] As a result, expression of PPARα mRNA was observed from 0.5 hour after the addition of NIK-333 (FIG. 1). Further, expression of PPARγ 1 mRNA was also observed from 0.5 hour after the addition of NIK-333 (FIG. 2), whilst expression of PPARγ 2 mRNA was not observed.

example 2

Ligand Activity for PPARα

[0026] COS-7 cells, a cell line derived from monkey kidney, were cultured at 37° C. in DMEM medium containing 10% fetal calf serum in the presence of 5% CO2. Then, expression vectors of RXRα (retinoic acid X receptor α) and PPAR a, and a reporter vector incorporated with PPRE (peroxisome proliferator-responsive element) as a PPAR-responsive element were cotransfected into the cells, and the cells were cultured for 24 hours. In order to examine the effect of NIK-333, a solution of NIK-333 or Wy-14643 (selective agonist of PPARα) in ethanol was added at a final concentration of 10 μM. After cultivation for 24 hours, the activity of firefly luciferase was measured. The measured values were represented as values standardized by using the renilla luciferase activity.

[0027] As shown in FIG. 3, NIK-333 and Wy-14643 failed to increase the luciferase activity when the PPARα expression vector was not introduced (−), whereas they increased the luciferase activity only...

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Abstract

Activators of peroxisome proliferator-activated receptors comprising a polyprenyl compound, preferably (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid, as an active ingredient, and medicaments for preventive and / or therapeutic treatment of hyperlipidemia, non-insulin dependent diabetes mellitus or the like comprising a polyprenyl compound as an active ingredient.

Description

TECHNICAL FIELD [0001] The present invention relates to an activator of peroxisome proliferator-activated receptors (abbreviated sometimes as “PPAR” in the specification). BACKGROUND ART [0002] Patients with hyperlipidemia or diabetes are estimated currently as 10 million or more in total in our country, and the number has been steadily increasing. Many of patients with diabetes suffer from non-insulin dependent diabetes mellitus, which is characterized by a pathological condition presenting hyperglycemia is resistant to the insulin action. Further, symptoms such as hyperinsulinemia, hypo HDL cholesterolemia, hypertension, and obesity most frequently occur with hyperlipidemia and diabetes, which raises clinical problems. In recent years, such pathological conditions presenting these multiple symptoms are referred to as Syndrome X, and considered as one of severe diseases (Reference: Diabetes, 37, 1595-1607 (1988)). [0003] As medicaments for therapeutic treatment of these diseases, c...

Claims

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Application Information

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IPC IPC(8): A61K31/202A61P3/06A61P3/10A61P43/00
CPCA61K31/202A61K31/20A61P3/10A61P3/06A61P43/00
InventorSHIDOJI, YOSHIHIROISHIBASHI, NAOTO
OwnerKOWA CO LTD