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Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level

a combination therapy and diabetes technology, applied in the field of diabetes and diabetes related conditions, can solve the problems of increasing the incidence of type 2 diabetes worldwide, increasing the risk of diabetes, so as to improve the condition, improve the condition, and reduce the risk of diabetes.

Inactive Publication Date: 2006-07-13
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a combination of a GPR119 agonist and a DPP-IV inhibitor for treating diabetes and related conditions. The combination can lower blood glucose levels in subjects with elevated blood glucose levels and increase GLP-1 levels in subjects with low GLP-1 levels. The invention also includes a method of screening for GLP-1 secretagogues using GPR119 agonists and DPP-IV inhibitors. The invention provides a new way to treat diabetes and related conditions by targeting GLP-1 and GLP-2 receptors.

Problems solved by technology

Type 2 diabetes causes significant morbidity and mortality at considerable expense to patients, their families and society.
Furthermore, the incidence of Type 2 diabetes worldwide is increasing such that Type 2 diabetes is now considered to be a worldwide epidemic.
Current GLP-1 peptide agonists suffer from a lack of oral bioavailability, negatively impacting patient compliance.
Because the incretin hormones are not the only substrates for DPP-IV, there is concern that inhibition of the cleavage of other endogenous DPP-IV substrates may give rise to undesirable side effects [see, e.g., Chen et al, J Biol Regul Homeost Agents (2004) 18:47-54, the disclosure of which is herein incorporated by reference in its entirety].

Method used

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  • Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
  • Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
  • Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synergistic Effect of GPR119 Agonist and DPP-IV Inhibitor in Lowering an Elevated Blood Glucose Level in Oral Glucose Tolerance Test (oGTT) in Mice

[0654] Oral glucose tolerance test (oGTT) in mice was carried out as described here. Overnight fasted mice (n=6 mice per treatment) were administered via oral gavage with vehicle (PET), a GPR119 agonist (AR231453) at 1 mkg (milligram compound per kilogram of body weight), a DPP-IV inhibitor (AR247810) at 0.1 mkg, or a combination of the GPR119 agonist (1 mkg) and the DPP-IV inhibitor (0.1 mkg). Thirty minutes later, a glucose bolus (3 gram / kg) was then delivered per orally. Plasma glucose levels were determined at the indicated time points over a two hour period using blood (˜5 μl) collected from tail nick and a glucose meter. Glycemic excursion curve was graphed based on data from 6 mice and given in mean values + / −SEM (FIG. 1A). Area Under Curve (AUC) of the glycemic excursion was calculated for each mouse and AUC inhibition (%) was re...

example 2

Combination of GPR119 Agonist and DPP-IV Inhibitor for Treating or Preventing Diabetes and Conditions Related Thereto

[0657] A GPR119 agonist in accordance with the present invention is selected. A DPP-IV inhibitor in accordance with the present invention is selected.

[0658] Titration of the GPR119 agonist with respect to percent inhibition of Area Under Curve (AUC) in mouse oral glucose tolerance test (oGTT) is determined across a dose range from about 0.01 mkg (milligram compound per kilogram of body weight) to about 100 mkg. See Example 1. A dose of the GPR119 agonist producing an AUC inhibition of glycemic excursion of about 15-20% is chosen. Typically, a dose of GPR119 agonist producing an AUC inhibition 30% or less is therapeutically ineffective in this mouse model.

[0659] Titration of the DPP-IV inhibitor with respect to percent inhibition of Area Under Curve (AUC) in mouse oral glucose tolerance test (oGTT) is determined across a dose range from about 0.01 mkg (milligram com...

example 3

Synergistic Effect of GPR119 Agonist and DPP-IV Inhibitor in Increasing a Blood GLP-1 Level after Glucose Challenge in Mice

[0663] C57blk / 6 male mice (8 weeks of age) were fasted for 18 hours, and randomly assigned into twelve groups with n=6 for each group. Mice were administered per orally with vehicle (PET), GPR119 agonist (10 mg / kg) DPP-IV inhibitor (1 mg / kg), or a combination of GPR119 agonist and DPP-IV inhibitor, as indicated. The GPR119 agonist (AR231453) and the DPP-IV inhibitor (AR247810) used here are identical to those used in Example 1. Thirty minutes after treatment, a glucose bolus at 3 g / kg were delivered per orally, and plasma were collected at 0 minute (no glucose bolus), and at 2 minutes and 5 minutes after glucose bolus. Plasma GLP-1 levels were determined by using a GLP-1 ELISA kit purchased from Linco Research Laboratory [Glucagon-Like Peptide-1 (Active) ELISA kit, Catalog #EGLP-35K].

[0664] Administration of a GPR119 agonist together with a DPP-IV inhibitor wa...

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Abstract

The present invention concerns combination of an amount of a GPR119 agonist with an amount of a dipeptidyl peptidase IV (DPP-IV) inhibitor such that the combination provides an effect in lowering a blood glucose level or in increasing a blood GLP-1 level in a subject over that provided by the amount of the GPR119 agonist or the amount of the DPP-IV inhibitor alone and the use of such a combination for treating or preventing diabetes and conditions related thereto or conditions ameliorated by increasing a blood GLP-1 level. The present invention also relates to the use of a G protein-coupled receptor to screen for GLP-1 secretagogues.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Ser. Nos. 60 / 643,086, filed Jan. 10, 2005, 60 / 683,172, filed May 19, 2005, and 60 / 726,880, filed Oct. 14, 2005, the disclosures of each of which are incorporated herein by reference in their entireties.FIELD OF THE INVENTION [0002] The present invention relates to compositions and methods for treating or preventing diabetes and conditions related thereto. The present invention further relates to compositions and methods for increasing a blood GLP-1 level in a mammal. The present invention also relates to methods of using a G protein-coupled receptor to screen for GLP-1 secretagogues. BACKGROUND OF THE INVENTION [0003] The following discussion is intended to facilitate the understanding of the invention, but is not intended nor admitted to be prior art to the invention. [0004] A. Diabetes [0005] Type 2 diabetes is one of the most common chronic diseases. Type 2 diabetes is characterized by fast...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/26A61K38/04C12Q1/68G01N33/53
CPCA61K31/00A61K31/401A61K31/415A61K31/4196A61K45/06G01N33/74G01N33/76G01N2333/726G01N2800/042G01N2800/2814G01N2800/2835G01N2800/2857G01N2800/2871A61K2300/00A61P1/14A61P1/18A61P13/12A61P17/02A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P27/12A61P3/00A61P3/04A61P3/06A61P43/00A61P5/48A61P9/00A61P9/08A61P9/10A61P9/12A61P3/10A61K38/17
Inventor CHU, ZHI-LIANGLEONARD, JAMESAL-SHAMMA, HUSSIENJONES, ROBERT
Owner ARENA PHARMA
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