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Application of dipeptide base peptidase IV effector for reducing blood sugar level of mammal

A dipeptidyl peptidase and mammalian technology, applied in the direction of active ingredients of heterocyclic compounds, medical preparations containing active ingredients, drug combinations, etc., can solve the problem of expensive transplantation and achieve pharmaceutically useful effects

Inactive Publication Date: 2006-08-16
PROSIDION LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, such transplants are expensive

Method used

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  • Application of dipeptide base peptidase IV effector for reducing blood sugar level of mammal
  • Application of dipeptide base peptidase IV effector for reducing blood sugar level of mammal
  • Application of dipeptide base peptidase IV effector for reducing blood sugar level of mammal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1. In vivo incretin GIP- 1-42 and GLP-1 7-36 Inhibition of DP IV-catalyzed hydrolysis

[0028] Hydrolysis of incretins by DP IV- and DP IV analogue-enzymatic activity, or its inhibition by inhibitors, could be demonstrated in vivo using purified enzymes or in situ using pooled human serum ( figure 1 ).

[0029] According to the present invention, in vivo by incubating 30 μM GIP 1-42 or 30 μM GLP-1 7-36 and 20 μM isoleucyl-tetrahydrothiazole (1a), within 24 hours to achieve complete inhibition of the enzymatic hydrolysis of the two peptide hormones (1b and 1c, each see the above spectrum), the incubation at pH7. Reversible DP IV-inhibitor in 20% pooled serum at 6 and 30°C. At pH 7.6 and 30°C, the synthetic gastric inhibitory polypeptide GIP 1-42 (5 μM) and synthetic GLP-1 7-36 (15 μM) were incubated with human serum (20%) in 0.1 mM TRICINE buffer for 24 hours. After various time intervals, samples for incubation analysis (for GIP 1-42 2.5pmol for GLP-1 ...

Embodiment 2

[0033] Example 2. Inhibition of GLP-1 by the DP IV-inhibitor isoleucyl-tetrahydrothiazole in vivo 7-36 Degradation

[0034] Compared with a control sample, the natural incretin (here GLP-1 7-36 ) dependence of the metabolism of the DP IV-inhibitor isoleucyl-tetrahydrothiazole (intravenous injection of 0.9% saline solution containing 1.5 μM inhibitor). In test animals (N=5) treated with inhibitors, the insulinotropic peptide hormone GLP-1 7-36 No degradation was observed during the experiment ( figure 2 ).

[0035] To detect metabolites of incretins in the presence and absence of DP IV-inhibitors, test and reference animals were given a further iv injection of 50-100 pM 20 min after initiation of iv administration of the inhibitor or saline 125 I-GLP-1 7-36 (approximately 1 μCi / pM specific activity). Blood samples were collected after 2-5 minutes of incubation, and protoplasts were extracted using 20% ​​acetonitrile. Subsequently, the peptide extracts were separated on ...

Embodiment 3

[0036] Example 3. Modulation of insulin action and reduction of blood glucose levels following intravenous administration of the DP IV-inhibitor isoleucyl-tetrahydrothiazole in vivo.

[0037] In mice stimulated by intraduodenal (i.d.) injection of glucose, by in vivo administration of different DP IV-effectors such as 0.1 mg of isoleucyl-tetrahydrothiazole per kg of mouse weight, observed attributable The temporally delayed onset of action of the inhibitor effect is a decrease in glucose levels. This effect was dose dependent and was reversible after cessation of injection of the DP IV-inhibitor isoleucyl-tetrahydrothiazole at 0.05 mg / min / kg rat weight. In contrast to intraduodenal glucose-stimulated test animals, no comparable effect was observed after intravenous administration of the same amount of glucose to inhibitor-treated and control animals. image 3 These inhibitor-dependent changes in protoplasm parameters are shown: A-DP IV-activity, B-protoplasm-insulin level, C-...

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Abstract

The invention relates to the use of a method in which by reducing in the blood of a mammal by administration of effectors the enzyme activity of dipeptidyl peptidase (DP IV) or enzyme activity similar to DP IV, the endogenous (or additionally exogenously administered) insulinotropic peptide gastric inhibitory polypeptide 1-42 (GIP1-42) and glucagon-like peptide amide-1 7-36 (GLP-17-36) (or similarly GLP-17-37 or analogues thereof) are decomposed in a causal sequence to a reduced extent by DP IV enzymes or those similar to DP IV. Consequently, the fall in the concentration of said peptide hormones or the analogues thereof is reduced or retarded. The increased stability, achieved by the action of DP IV effectors, of the incretine or the analogues thereof which are available endogenously or exogenously and consequently provided in increased numbers for insulinotropic stimulation of the incretine receptors of the Langerhans cells in the pancreas, changes the power of endogenous insulin thereby stimulating the metabolism of carbohydrates in the treated organism. The blood sugar level therefore drops below the glucose concentration, characteristic of hyperglycaemia, in the serum of the treated organism.

Description

[0001] The present invention is a divisional application of a Chinese patent application with an application date of April 24, 1997, an application number of 97194017.7, and an invention title of use of dipeptidyl peptidase IV effectors for lowering blood sugar levels in mammals. technical field [0002] The present invention relates to a simple method for lowering blood glucose concentration by means of effectors (substrates, pseudosubstrates, inhibitors) that inhibit enzymes having similar or identical activity to the enzymatic activity of dipeptidyl peptidase IV. agents, binding proteins, antibodies, and their analogs) to lower blood glucose concentrations. Background technique [0003] In addition to proteases associated with non-specific proteolysis, proteases leading to protein-specific degradation are well known, which are associated with functional regulation (activation, inactivation or regulation) of endogenous peptides [KIRSCHKE, H., LANGNER, J RIEMANN, S., WIEDER...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/55A61K31/426A61K39/395A61P3/10A61P3/06C07D277/04A61K31/00A61K31/40A61K31/401A61K31/425A61K38/00A61K38/46A61K45/00
CPCA61K31/401A61K31/00A61K31/40A61K31/426A61P3/00A61P3/10A61P3/12A61P3/06A61P3/08A61P43/00A61P5/50A61K31/425
Inventor H-U·德姆思F·罗施J·施密德R·P·帕里C·H·S·麦克恩多什R·A·佩德逊
Owner PROSIDION LIMITED
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