WO2008056726A1 - Dérivé de glp-1 et son utilisation - Google Patents

Dérivé de glp-1 et son utilisation Download PDF

Info

Publication number
WO2008056726A1
WO2008056726A1 PCT/JP2007/071687 JP2007071687W WO2008056726A1 WO 2008056726 A1 WO2008056726 A1 WO 2008056726A1 JP 2007071687 W JP2007071687 W JP 2007071687W WO 2008056726 A1 WO2008056726 A1 WO 2008056726A1
Authority
WO
WIPO (PCT)
Prior art keywords
glp
derivative
lys
amino acid
peptide
Prior art date
Application number
PCT/JP2007/071687
Other languages
English (en)
Japanese (ja)
Inventor
Takahito Jomori
Yuji Hayashi
Mitsuhiro Makino
Original Assignee
Sanwa Kagaku Kenkyusho Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanwa Kagaku Kenkyusho Co., Ltd. filed Critical Sanwa Kagaku Kenkyusho Co., Ltd.
Publication of WO2008056726A1 publication Critical patent/WO2008056726A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a human glucagon-like peptide-1 (GL P-1; Glucagon like peptide-1) known as an incretin hormone. Specifically, the present invention has a high absorbability from mucous membranes. It is an invention of a novel derivative of GLP-1.
  • GLP-1 is known as an incretin hormone that is secreted from the gastrointestinal tract by food intake and works on the viscera to stimulate insulin secretion.
  • GIP Gas trie lnhioitory polypeptide or 7 lucose-depenaent insulinotropic polypeptide
  • GIP has the same effect: Does the type 2 diabetes patient lack this incretin effect compared to healthy individuals? It is also suggested that the disorder is one of the causes of hyperglycemia, for example, blood GLP-1 levels are decreased in patients with type 2 diabetes and GIP is different from that of healthy individuals.
  • Incretin hormone administration test for type 2 diabetic patients showed that GLP-1 administration did not show any difference in insulin secretion promoting response compared to healthy subjects, but GIP administration As a result, it has been reported that the response to GLP-1 is maintained in diabetic patients.
  • the insulin secretion action of GLP-1 is characterized by glucose level dependency that insulin secretion is not stimulated when blood glucose level is 110 mg / dl or less, and insulin is secreted only when blood glucose level is higher than that. Is to represent. That is, administration of GLP-1 promotes insulin secretion according to blood glucose level, and insulin secretion does not occur when blood glucose level is below normal. Therefore, when GLP-1 is used, there are no significant concerns about hypoglycemia, and the great clinical merit is not to exhaust the viscera due to excessive insulin secretion.
  • sulfonylurea which has been used mainly for the treatment of type 2 diabetes, continuously closes ATP-sensitive K + channels and promotes insulin secretion.
  • GLP-1 the active body of GLP-1 is a polypeptide of GLP-1 (7-36) amide or GLP_1 (7_37).
  • GLP-1 is taken orally, it is digested and degraded by digestive enzymes in the digestive tract. Is not absorbed. Therefore, in clinical practice, intravenous injection or subcutaneous injection by infusion is being attempted.
  • GLP-1 is also degraded by dipeptidyl peptidase IV (DPPIV) present in blood and tissues, and the in vivo half-life is known to be very short; 2 to 2 minutes. These are the bottlenecks for clinical application.
  • DPPIV dipeptidyl peptidase IV
  • Dipeptidyl peptidase IV known as an enzyme that degrades GLP-1, is widely distributed in the kidney, liver, small intestine, salivary gland, various connective tissues, and other body fluids such as blood, urine, saliva, and nasal passages. It is becoming clear that it also exists in the mucosa.
  • Type GLP-1 injection (development name Liraglutide), or GLP-1 derivative with long-lived half-life that binds albumin in vivo (development number CJC-1131; Diabetes 52 (3) : 751_759 (2003))
  • development number CJC-1131 development number CJC-1131; Diabetes 52 (3) : 751_759 (2003)
  • synthetic exendin-4 injection product name
  • GLP-1 is widely used as a treatment for diabetes.
  • administration routes other than injection are desirable.
  • WO2004 / 037859 the present inventors increase GLP-1 mucosal absorption including nasal mucosa by directly adding several arginine or lysine to the C-terminus of GLP-1. I found out.
  • WO2001 / 004156 discloses [Gly 8 ] -GLP-1 (7_36)-(Lys) -NH.
  • Patent Literature l WO2004 / 037859
  • Patent Document 2 WO2001 / 004156
  • Non-patent literature l Diabetologia 41: 271-278 (1998)
  • Non-Patent Document 2 Biochem 40: 2860-2869 (2001)
  • Non-Patent Document 3 Diabetes 52 (3): 751_759 (2003)
  • GLP-1 Absorption of GLP-1 from the mucosa is much less efficient than injection due to low membrane permeability and degradation at the site of absorption.
  • the present inventors increased mucosal absorption of GLP-1 derivatives by directly adding several arginine (A rg) or lysine (Lys) to the C-terminus of GLP-1. I found out.
  • the sequence added to the C-terminal side is a structure in which lysine is continuous.
  • (Lys) n-Arg (n is an integer of 4 to 8, Arg is a carboxylic acid form) is added to the C-terminus of a peptide having a GLP-1 activity.
  • the present invention comprises GLP-7-35) or GLP-7-36) amino acid sequences, or a sequence having 85% or more homology with those amino acid sequences, and A peptide in which (Lys) n-Arg (n is an integer of 4 to 8, Arg is a carboxylic acid form) is added to the C-terminus of the peptide having GLP-1 activity.
  • alanine (Ala) at position 8 of natural GLP-1 is converted to serine (Ser) or glycine (G1 y ) Is preferred.
  • trypsin resistance can be achieved by substituting lysine at position 26 with glutamine (Gin) and lysine at position 34 with asparagine (Asn) or aspartate (Asp).
  • the number n of lysine residues added to the C-terminal is preferably 4 to 6, and most preferably 5.
  • the most preferred GLP-1 derivative of the present invention is represented by [Ser 8 ] -GLP-l (7-35)-(Lys) -Arg (Arg is a carboxylic acid form).
  • the present invention also relates to a pharmaceutical composition comprising the GLP-1 derivative of the present invention as an active ingredient.
  • the pharmaceutical composition of the present invention is suitable for transmucosal administration, particularly nasal administration.
  • the pharmaceutical composition of the present invention can be used for the treatment of diabetes, the treatment of obesity, the suppression of appetite, or the suppression of heart disease.
  • the peptide of the present invention can be used for producing a therapeutic agent for diabetes, obesity or eating disorders.
  • the GLP-1 derivative of the present invention has a continuous structure of lysine and / or arginine on the C-terminal side described in WO2004 / 037859, which is not limited to natural GLP-1. It has a much higher mucosal absorption rate than some GLP-1 derivatives. Therefore, the GLP-1 derivative of the present invention greatly enhances the possibility of clinical application of a mucosal absorption type GLP-1 preparation that is easy to administer and is not painful in place of conventional injections. It is considered to be very useful for improving the quality of life of patients, obese patients, and patients with heart disease.
  • the GLP-1 derivative of the present invention has an added lysine moiety that is readily cleaved in blood immediately after being decomposed by a protease and is present in a form close to that of natural GLP-1.
  • the sex is also considered extremely low.
  • GLP-1 (7-36) is His-Ala-Glu-Gly-Thr-Phe_Thr_Ser_Asp_Val_Ser_Ser_Tyr_Leu_Glu_Gly_Gln_Ala_Ala_Lys_Glu_Phe_Ile_Ala-Trp-Leu-Va ⁇ Lys-Gly-Aly Lys-Gly-Aly [Ser 8 ] indicates that the second, that is, 8-position alanine in the sequence is converted to serine, and is synonymous with 8S.
  • the GLP-1 derivative it is possible to take the form of either an amide form in which the C-terminus of the amino acid is amidated, an amidated form! /, Na! /, Or a carboxylic acid form! / is there.
  • the power of natural GLP-1 is an amide.
  • the GLP-1 derivative of the present invention is a carboxylic acid.
  • -NH represents an amide form
  • -COOH represents a carboxylic acid form.
  • the present invention is the first example showing that the effect of transmucosal administration is higher when the carboxylate of the amino acid of the GLP-1 derivative is carboxylic acid than when it is amide.
  • the GLP-1 derivative of the present invention lacks GLP-K7-35) or GLP-K7-36) amino acid sequence, or one or several amino acids thereof.
  • (Lys) n — Arg (n is an integer from 4 to 8, Arg is a carboxylic acid form) is added to the C-terminus of a peptide having a lost, substituted and / or added sequence and having GLP-1 activity.
  • Peptide is an integer from 4 to 8
  • GLP-1 mutants are not lost even if some amino acids of the native GLP-1 peptide are deleted, substituted and / or added. is there.
  • Such a GLP-1 variant can be expressed in another way! /, From a sequence having 85% or more homology with the amino acid sequence of GLP-K7-35) or GLP-K7-36). And can be expressed as a peptide having GLP-1 activity.
  • Many of these natural GLP-1 peptide variants are It is technical common sense that there are numbers. Specifically, alanine at position 8 may be substituted with serine or glycine, which adds resistance to dipeptidyl peptidase IV.
  • lysine at position 26 may be substituted with glutamine, and lysine at position 34 may be substituted with asparagine or aspartic acid.
  • parin at position 16, serine at position 17, serine at position 18, glycine at position 22, glutamic acid at position 27, lysine at position 34, arginine at position 36 can each be substituted with alanine, and at the same time at least two can be substituted with alanine. It has been.
  • GLP-1 mutants can be exemplified as follows based on the sequence of GLP-K7-35) or GLP-K7-36).
  • GLP-K7-35) or GLP-K7-36) substitute for serine or glycine at position 8, substitute for glutamine at position 26, substitute for asparagine or aspartate at position 34, and these 8 A combination of two or more of the substitutions at positions 26, 34, and further, a substitute for alanine at position 16, a substitute for alanine at position 17, a substitute for alanine at position 18 , Substitution to alanine at position 22, substitution to alanine at position 27, substitution to alanine at position 34, substitution to alanine at position 36, and substitution from alanine at positions 16 to 36 A combination of two replacements.
  • the GLP-1 derivative of the present invention can be produced in the same manner as in WO2004 / 037859 by chemical synthesis or gene recombination techniques.
  • the principles of chemical synthesis of polypeptides are well known in the art, and general texts in this area can be consulted as follows: Dugas ⁇ ⁇ and Penney C, Bioorganic (chemistry (1981) springer- Verlag, New York, 54-92 shells, f row ;, m odd 430A heptad synthesizer (Applied Biosystems Inc, 850 Lincoln Center Drive, Foster City CA 94404) and a solid phase using a synthesis cycle supplied by PE-Applied Biosystems.
  • the peptides of the present invention can be synthesized by methods Boc amino acids and other reagents can be purchased from Applied Biosystems and other drug suppliers.
  • a method for producing the peptide of the present invention by a gene recombination technique is as follows.
  • GLP-1 DNA can be obtained by total synthesis or by modification of DNA encoded by a larger natural glucagon.
  • the DNA sequence encoding the prebloglucagon is shown in Lund et al. [Proc Natl Acad Sci USA 79: 345-349 (1982)]. And can be used for the production of the compounds of the present invention.
  • Methods for constructing synthetic genes are well known in the art, see Brown et al., Methods in Enzymology, Academic Press, NY Volume 68, pages 109-151.
  • a DNA sequence encoding the peptide of the present invention is designed based on the amino acid sequence, and Model 3400 DNA synthesizer or ABI3900 high throughput nucleus' acid synthesizer (Applied Biosystems Inc, 850 Lincoln Center Drive, Foster City CA 94 404)
  • a DNA having the sequence itself can be produced using a normal DNA synthesizer such as.
  • the DNA used for the production of the GLP-1 derivative of the present invention has a device that increases the expression level and stably accumulates the product in the host, a device that facilitates purification after production, or a fusion tank. It can be produced as ⁇ and can be devised to easily cut out the GLP-1 derivative.
  • the target GLP-1 derivative can be obtained by performing purification using a fused protein and then cleaving with a specific protease.
  • the GLP-1 derivative gene prepared as described above is inserted into an appropriate recombinant DNA expression vector using an appropriate restriction endonuclease according to a common sense technique in this field.
  • an appropriate restriction endonuclease for the effective expression method of GLP-1 derivative peptides at that time and various expression vectors that can be used for transformation in prokaryotic cells and eukaryotic cells, general methods in this region can be referred to. (Maniatis et al. (1989) Molecular Cloning; A Laboratory Manual, Cold Springs Harbor Laboratory Press, NY Volumes 1-3 and The Promega Biological Research Products Catalog and The Stratagene Cloning Systems Catalog).
  • Host cells can be either eukaryotic cells or prokaryotic cells! /. Techniques for transforming cells are well known in the art and can be found in general citations such as Maniatis et al. Prokaryotic host cells are generally more Produces protein at a high rate and is easier to culture. Proteins expressed in high level bacterial expression systems characteristically aggregate into particles or inclusion bodies that contain high levels of overexpressed protein. Such typically aggregated proteins are solubilized, denatured and refolded using techniques well known in the art. See Protein Folding, Kreuger et al. (1990) pages 136-142, edited by Gierasch and King, American Association for Advancement of science Publication.
  • the compound of the present invention can be formulated into a pharmaceutical composition by combining with a pharmaceutically acceptable carrier, diluent, excipient or absorption enhancer.
  • Absorption enhancers include, for example, chelating agents (eg, EDTA, citrate, salicylate), surfactants (eg, sodium dodecyl sulfate (SDS)), non-surfactants (eg, unsaturated cyclic urea), And bile acid salts (for example, sodium deoxycholate, sodium taurocholate).
  • chelating agents eg, EDTA, citrate, salicylate
  • surfactants eg, sodium dodecyl sulfate (SDS)
  • non-surfactants eg, unsaturated cyclic urea
  • bile acid salts for example, sodium deoxycholate, sodium taurocholate.
  • Such a pharmaceutical composition can be produced by a well-known method in the pharmaceutical field.
  • these pharmaceutical compositions are suitable
  • compositions of the invention can be formulated using methods well known in the art to provide the patient with a rapid, sustained or delayed release of the active ingredient after administration.
  • suitable macromolecules eg, polyesters, polyamino acids, polybutyrolipidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose and protamine sulfate
  • polyesters polyamino acids, hydrated gels, polylactic acid, polydaricholic acid, lactic acid
  • the peptide of the present invention is complexed or adsorbed with the peptide of the present invention to produce a controlled release formulation be able to.
  • microcapsules manufactured by coacervation technology or interfacial polymerization
  • microcapsules made of hydroxymethylcellulose or gelatin colloidal drug delivery systems (for example, Ribosome, albumin microsphere, microemulsion, nanoparticle and nanocapsule) or the microemulsion can encapsulate the peptide of the present invention.
  • the GLP-1 derivative of the present invention is effective for various diseases for which a GLP-1 preparation is effective. That is
  • the GLP-1 derivative of the present invention can be used, for example, for the treatment of non-insulin dependent diabetes, the treatment of insulin dependent diabetes, the treatment of obesity, the suppression of appetite, or the suppression of heart disease. .
  • the dosage of the GLP-1 derivative of the present invention is desirably determined by those skilled in the art for individual patients with various diseases. In general, however, the dosage will be in the range of 1 ⁇ g to 1 mg per kg of body weight, preferably in the range of 10 ⁇ g to 100 ⁇ g per kg of body weight. It can be used immediately before meals and administered once to three or more times a day.
  • the GLP-1 derivative was synthesized by solid phase synthesis using a Model 433A peptide synthesizer (Applied Biosystems, Foster City, Calif.), Purified by HPLC, and the synthesized product was confirmed by mass spectrum. Purity was over 95% for the majority, and was tested in vitro and in vivo. The synthesized compounds and their abbreviations are shown below.
  • GLP-1 derivative of the present invention the peptides of Production Examples 1 and 2 were synthesized.
  • the GLP-1 derivative of the present invention can be synthesized based on the GLP-1 mutant described in paragraphs 18 and 19.
  • Comparative Production Examples 3 to 6 are peptides and their substitutes described in WO2004 / 037859, and Comparative Production Examples 7 to 10 are described in WO2001 / 004156. Peptides and their substitutes
  • Test Examples 1 In 1 to 16, various GLP-1 derivatives were administered nasally to mice, and oral glucose tolerance test (OGTT) was conducted to investigate changes in blood glucose levels after oral loading with Darcos. The efficacy was compared.
  • OGTT oral glucose tolerance test
  • GLP-1 derivatives were prepared in ImM with distilled water and stocked at _80 ° C. At the time of the test, it was diluted to a predetermined concentration with physiological saline and used. Using a micropipette, 20 ⁇ 1 GLP-1 derivative solution is slowly released directly from the tip of the tip directly into the mouse's nose using a micropipette. It was aspirated from the nose. Five minutes after the nasal administration of the GLP-1 derivative, a 10% glucose solution was orally administered with a sonde at a rate of 10 ml / kg.
  • blood sample 1 was squeezed from the wound where the tip of the tail was excised over time immediately after the test and after glucose administration, using a small blood glucose meter (Daltest Neo, Sanwa Chemical Laboratory Co., Ltd.). Measured. The area under the curve (AUC 0-20 minutes or 0-120 minutes) from the blood glucose level before administration in each GLP-1 derivative administration group was calculated.
  • GLP-1 derivative 8S-GLP-l (7_35) + 5KR-COOH from Production Example 1 and GLP-1 derivative 8S-GLP-1 (7_35) + 5KR-NH from Comparative Production Example 3 were each 1 nmol / Administration by mouse and comparison of efficacy.
  • As a control group 1 and 10 nmol / mouse of GLP-K7-3 6) -NH, which is a natural GLP-1 of Comparative Production Example 1, were set.
  • the GLP-1 derivative of Comparative Production Example 3 is one of the most active GLP-1 derivatives in W 02004/037859.
  • GLP-1 derivative 8S-GLP-l (7_36) + 4R-COOH from Comparative Production Example 5 and GLP-1 derivative 8S-GLP-1 (7_36) + 4R-NH from Comparative Production Example 6 are each 1 nmol. Administered with / mouse and compared efficacy. As a control group, 1 and 10 nmol / mouse of GLP-1 (7-36) _NH of Comparative Production Example 1 were set.
  • the GLP-1 derivative of Comparative Production Example 6 is one of the most active GLP-1 derivatives in WO2004 / 037859, and Comparative Production Example 5 is its C-terminal carboxylic acid form.
  • Test Example 1 3 Here, 8S-GLP-l (7-35) + 5KR-COOH and 8S-GLP-l (7-36) + 4R-COOH, which were highly active in Test Example 1 1 and Test Example 1 2, respectively Administration was performed at 0 ⁇ 3, 1 and 3 nmol / mouse to compare the efficacy. As a control group, 10 nmol / mouse of GLP-1 (7-36) _NH was set.
  • the GLP-1 derivative of Comparative Production Example 8 is the 8-position serine of the GLP-1 derivative described in WO2001 / 004156, and Comparative Production Example 7 is its C-terminal carboxylic acid form.
  • GLP-1 derivative 8S-GLP-l (7_35) + 5KR-COOH from Production Example 1 and GLP-1 derivative 8G-GLP-1 (7_36) + 6K-NH from Comparative Production Example 10 are 0.3 and 1 respectively. And 3 nmol / mouse to compare the efficacy.
  • OOH was 1.6 nmol / mouse, 8G-GLP-1 (7_36) + 6K-NH power 9 nmol / mouse, and the ratio was 3.1 times.
  • GLP-1 derivatives were administered intranasally to mice, and their blood kinetics and absorption rate were examined.
  • the administered GLP-1 derivative was 8S-GLP-l (7_35) + 5KR-COOH of Production Example 1, and was administered at 30 and lOOnmol / kg.
  • natural GLP_1 (7_36) -NH from Comparative Production Example 1 and GLP-1 derivative 8S-GLP-1 (7-36) _NH from Comparative Production Example 2 were administered at 100 and 300 ⁇ mol / kg, respectively. .
  • mice were ddY mice (7 weeks, male), and 100 1 was collected from the orbital venous plexus using a heparin-treated glass capillary immediately before nasal administration of the GLP-1 derivative.
  • the blood GLP-1 concentration was defined as the value at 0 minutes after administration.
  • the mice were lightly anesthetized with ether, and 20 1 GLP-1 derivative solution was slowly released from the tip of the pipette tip directly into the nose of the mouse using a micropipette. Thereafter, 100 blood samples were collected from the orbital venous plexus over time, and plasma was obtained by centrifuge separation. Plasma GLP-1 concentration was measured using the GLP-l (total) RIA kit (LINCO, Ca t No. GLP1T-36HK) to determine the absorption rate.
  • the absorption rate indicates the absorption rate by nasal administration of each GLP-1 derivative when the absorption when each GLP-1 derivative was intravenously administered was taken as 100%.
  • Table 1 shows the absorption rate of GLP-1 derivatives.
  • 8S-GLP-K7-35) + 5KR-COOH which is a GLP-1 derivative of the present invention, is a natural GLP-1 (7_36) -NH or 8S ⁇ It was found that the same blood concentration could be achieved with almost 1/3 dose of GLP-l (7-36) -NH. Comparing the absorption rate at the same dose of 100 nmol / kg, 8S-GLP-1 (7_35) + 5K R-COOH is the natural GLP-1 (7-36) _NH and 8S-GLP-1 (7_36) The absorption rate was almost 6 times higher than that of -NH.
  • FIG.1 Comparison of the blood glucose lowering effects of 8S-GLP-l (7_35) + 5KR-COOH and 8S-GLP-1 (7_35) + 5KR-NH by nasal administration in Test Example 1 1! It is a figure which shows the result. In the figure, the number in brackets after the compound abbreviation name indicates the dose (nmol / mouse).

Abstract

[PROBLÈMES] Proposer un nouveau dérivé de GLP-1 ayant une capacité améliorée de façon importante d'être absorbée à travers une membrane muqueuse [MOYENS POUR RÉSOUDRE LES PROBLÈMES] L'invention concerne un peptide qui a (Lys)n-Arg [où n représente un entier de 4 à 8, et Arg est sous la forme d'un acide carboxylique] ajouté à l'extrémité C terminale d'un peptide comprenant une séquence d'acides aminés correspondant à GLP-1 (7-35) ou GLP-1 (7-36) ou une séquence d'acides aminés ayant la délétion, substitution et/ou addition d'un ou plusieurs résidus d'acide aminé dans la séquence d'acides aminés mentionnée ci-dessus, ayant au moins 85 % d'homologie avec la séquence d'acides aminés mentionnée ci-dessus et ayant une activité GLP-1. Le résidu d'acide aminé en position 8 dans la séquence d'acides aminés pour GLP-1 est, de préférence, la sérine ou la glycine, et l'entier “n” est, de préférence, 5.
PCT/JP2007/071687 2006-11-09 2007-11-08 Dérivé de glp-1 et son utilisation WO2008056726A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006304380A JP2010043001A (ja) 2006-11-09 2006-11-09 Ｇｌｐ−１誘導体とその用途
JP2006-304380 2006-11-09

Publications (1)

Publication Number Publication Date
WO2008056726A1 true WO2008056726A1 (fr) 2008-05-15

Family

ID=39364537

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/071687 WO2008056726A1 (fr) 2006-11-09 2007-11-08 Dérivé de glp-1 et son utilisation

Country Status (2)

Country Link
JP (1) JP2010043001A (fr)
WO (1) WO2008056726A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN103087174A (zh) * 2011-11-03 2013-05-08 华东师范大学 一种glp-1衍生物dlg3312及其固相化学合成方法
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2016035820A1 (ja) * 2014-09-02 2017-06-22 学校法人東京理科大学 中枢作用性ペプチド誘導体及び医薬組成物

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5545618A (en) * 1990-01-24 1996-08-13 Buckley; Douglas I. GLP-1 analogs useful for diabetes treatment
WO2001004156A1 (fr) * 1999-07-12 2001-01-18 Zealand Pharmaceuticals A/S Peptides abaissant les niveaux de glycemie
JP2001516765A (ja) * 1997-09-12 2001-10-02 ヴォルフ ゲオルグ フォースマン 真性糖尿病及び肥満の治療のための組成物
JP2002508162A (ja) * 1998-02-27 2002-03-19 ノボ ノルディスク アクティーゼルスカブ Ｎ末端を短縮したｇｌｐ−１誘導体
WO2004003759A1 (fr) * 2002-06-27 2004-01-08 Nazomi Communicatons, Inc. Processeurs d'applications et architecture de memoire pour applications sans fil
WO2005027978A2 (fr) * 2003-09-19 2005-03-31 Novo Nordisk A/S Nouveaux derives de glp-1
WO2005028516A2 (fr) * 2003-09-19 2005-03-31 Novo Nordisk A/S Nouvelles etiquettes d'affinite pour les proteines plasmiques
WO2005065714A1 (fr) * 2003-12-26 2005-07-21 Nastech Pharmaceutical Company Inc. Administration intranasale de peptides regulant le glucose
JP2005523877A (ja) * 2001-10-01 2005-08-11 イーライ・リリー・アンド・カンパニー 重病に関連する死亡率および罹患率の低減化方法
WO2005085458A2 (fr) * 2004-02-27 2005-09-15 Nitto Denko Corporation Compositions et procedes pour une transfection mediee par un peptide polymere biodegradable

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5545618A (en) * 1990-01-24 1996-08-13 Buckley; Douglas I. GLP-1 analogs useful for diabetes treatment
JP2001516765A (ja) * 1997-09-12 2001-10-02 ヴォルフ ゲオルグ フォースマン 真性糖尿病及び肥満の治療のための組成物
JP2002508162A (ja) * 1998-02-27 2002-03-19 ノボ ノルディスク アクティーゼルスカブ Ｎ末端を短縮したｇｌｐ−１誘導体
WO2001004156A1 (fr) * 1999-07-12 2001-01-18 Zealand Pharmaceuticals A/S Peptides abaissant les niveaux de glycemie
JP2005523877A (ja) * 2001-10-01 2005-08-11 イーライ・リリー・アンド・カンパニー 重病に関連する死亡率および罹患率の低減化方法
WO2004003759A1 (fr) * 2002-06-27 2004-01-08 Nazomi Communicatons, Inc. Processeurs d'applications et architecture de memoire pour applications sans fil
WO2005027978A2 (fr) * 2003-09-19 2005-03-31 Novo Nordisk A/S Nouveaux derives de glp-1
WO2005028516A2 (fr) * 2003-09-19 2005-03-31 Novo Nordisk A/S Nouvelles etiquettes d'affinite pour les proteines plasmiques
WO2005065714A1 (fr) * 2003-12-26 2005-07-21 Nastech Pharmaceutical Company Inc. Administration intranasale de peptides regulant le glucose
WO2005085458A2 (fr) * 2004-02-27 2005-09-15 Nitto Denko Corporation Compositions et procedes pour une transfection mediee par un peptide polymere biodegradable

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN103087174A (zh) * 2011-11-03 2013-05-08 华东师范大学 一种glp-1衍生物dlg3312及其固相化学合成方法
CN103087174B (zh) * 2011-11-03 2015-11-18 华东师范大学 一种glp-1衍生物dlg3312及其固相化学合成方法
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

Also Published As

Publication number Publication date
JP2010043001A (ja) 2010-02-25

Similar Documents

Publication Publication Date Title
WO2008056726A1 (fr) Dérivé de glp-1 et son utilisation
JP6229038B2 (ja) 修飾された血管作動性腸管ペプチド
AU2003272970B2 (en) GLP-1 derivatives and transmicosal absorption preparations thereof
TWI547499B (zh) 胰高血糖素/glp-1受體協同激動劑
JP5657230B2 (ja) Ｇｌｐ−１分子の投与方法
EP0964873B1 (fr) Utilisation du peptide-1 semblable au glucagon-1 (glp-1) ou de ses analogues pour supprimer les modifications cataboliques postoperatoires
JP7461997B2 (ja) 制御放出および持続的放出のためのｅｌｐ融合タンパク質
TWI353250B (en) Glp-1 pharmaceutical compositions
JP2002509078A (ja) エキセンジンおよびｇｌｐ−１の変力および利尿効果
CN103596595A (zh) 用于治疗糖尿病的包括长效胰岛素缀合物和长效促胰岛素肽缀合物的组合物
WO2011109787A1 (fr) Méthodes d'administration de peptides insulinotropes
US20100298213A1 (en) Pharmaceutically Active Insulin Receptor-Modulating Molecules
CZ165199A3 (cs) Léčivo k redukci tělesné hmotnosti nebo obezity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07831418

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07831418

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP