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Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto

An osteoporosis, agonist technology, applied in the field of GPR119 receptor agonists, can solve the problems of lack of oral bioavailability and affecting patient compliance

Inactive Publication Date: 2009-04-29
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current GIP peptide agonists suffer from a lack of oral bioavailability, thus negatively impacting patient compliance

Method used

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  • Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
  • Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
  • Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0922] Example 1: Pharmacodynamic analysis of the effect of administration of GPR119 agonists on blood GIP levels in wild-type mice

[0923] A. C57blk / 6 male mice were fasted for 18 hours and randomly assigned to 14 groups, n=6 for each group. With vehicle (PET; 80% PEG400, 10% ethanol, 10% Tween80) or with 20 mg / kg of GPR119 agonist according to the invention (compound 1Z; (2-fluoro-4-methanesulfonyl-phenyl) -{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}- amines) were administered orally to mice (as shown in Figure 1A). At 30 minutes post-treatment, a 3 g / kg glucose bolus was delivered orally, and at 0 minutes (no glucose bolus), 2 minutes, 5 minutes, 10 minutes, 20 minutes, 40 minutes, and 60 minutes after the glucose bolus. Plasma was collected at 1 min. By using the Rodent GIP ELISA Kit [Rat / Mouse Gastric Inhibitory Polypeptide (Total) ELISA, Catalog No. EZRMGIP-55K] purchased from Linco Research Laboratory (Linco Research Laboratory)...

example 2

[0926] Example 2: Effect of Administration of a GPR119 Agonist on Blood GIP Levels in GPR119 Deficient (Knockout) Mice Compared to Wild Type Mice

[0927]A. GPR119-null male mice and wild-type littermates were fasted for 18 hours. With vehicle (PET; 80% PEG400, 10% ethanol, 10% Tween80) or with 20 mg / kg of GPR119 agonist according to the invention (compound 1Z; (2-fluoro-4-methanesulfonyl-phenyl) -{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}- amines) were administered orally to mice (as indicated (n=5)). At 30 minutes post-treatment, blood (100 microliters) was collected via the retro-orbital vein of the eye (time 0), followed by administration of a 3 g / kg glucose bolus (po). Another blood sample (100 microliters) was collected 5 minutes after the glucose delivery (time 5 minutes). Plasma was collected after centrifugation and analyzed by using the Rodent GIP ELISA Kit [Rat / Mouse Gastric Inhibitory Polypeptide (Total) ELISA, Cat. No. EZR...

example 3

[0929] Example 3: Effect of Administration of a GPR119 Agonist in Combination with a DPP-IV Inhibitor on Blood GIP Levels in Wild-Type Mice

[0930] Using the in vivo assays described below, it can be shown that an amount of a GPR119 agonist in combination with an amount of a DPP-IV inhibitor according to the invention increases the GIP content in the blood of an individual.

[0931] C57blk / 6 male mice were fasted for 18 hours and randomly assigned to 14 groups, n=6 for each group. Mice were orally dosed with vehicle (PET; 80% PEG400, 10% ethanol, 10% Tween80) or a combination of an amount of GPR119 agonist and an amount of DPP-IV inhibitor. The experimental group was similar to that of Example 1 above. Each of the combined GPR119 agonist and DPP-IV inhibitor is used in an amount between 0.001 mg / kg body weight and 100 mg / kg body weight. At 30 minutes post-treatment, a 3 g / kg glucose bolus was delivered orally, and at 0 minutes (no glucose bolus), 2 minutes, 5 minutes, 10 mi...

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Abstract

The present invention relates to the use of GPR119 receptor agonists for treating or preventing a condition characterized by low bone mass, such as osteoporosis, and for increasing bone mass in an individual. The present invention further relates to the use of a GPR119 receptor agonist in combination with a dipeptidyl peptidase IV (DPP-IV) inhibitor for treating or preventing a condition characterized by low bone mass, such as osteoporosis, and for increasing bone mass in an individual. A GPR119 receptor agonist and the combination of a GPR119 receptor agonist and a DPP-IV inhibitor promote bone formation in an individual.

Description

technical field [0001] The present invention relates to the use of GPR119 receptor agonists for the treatment or prevention of conditions characterized by low bone mass, such as osteoporosis, and for increasing bone mass in an individual. The present invention also relates to combinations of GPR119 receptor agonists and dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment or prevention of conditions characterized by low bone mass (such as osteoporosis) and for increasing the Use of bone mass. GPR119 receptor agonists and combinations of GPR119 receptor agonists and DPP-IV inhibitors promote bone formation in a subject. Background technique [0002] The following discussion is intended to facilitate an understanding of the invention, but is not intended to be admitted as background art to the invention. [0003] A) osteoporosis [0004] Osteoporosis is a disabling disease characterized by loss of bone mass leading to reduced bone strength and microarchitectural de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00A61K31/4375A61K31/4439A61K31/4545A61K31/505A61K31/506A61K31/519A61K31/522A61K45/06A61P19/02A61P19/08A61P19/10
Inventor 褚志亮詹姆斯·N·伦纳德于尔格·莱曼罗伯特·M·琼斯
Owner ARENA PHARMA
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