WO1997040832A1 - Verwendung von dipeptidyl peptidase iv effektoren zur senkung des blutglukosespiegels in säugern - Google Patents
Verwendung von dipeptidyl peptidase iv effektoren zur senkung des blutglukosespiegels in säugern Download PDFInfo
- Publication number
- WO1997040832A1 WO1997040832A1 PCT/DE1997/000820 DE9700820W WO9740832A1 WO 1997040832 A1 WO1997040832 A1 WO 1997040832A1 DE 9700820 W DE9700820 W DE 9700820W WO 9740832 A1 WO9740832 A1 WO 9740832A1
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- WIPO (PCT)
- Prior art keywords
- effectors
- blood
- glucose
- enzyme activity
- dipeptidyl peptidase
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
Definitions
- the invention relates to a simple method for lowering the blood sugar concentration with the aid of activity-reducing effectors (substrates, pseudo-substrates, inhibitors, binding proteins, antibodies, etc.) for enzymes with comparable or identical activity to the enzymatic activity of the enzyme dipeptidyl peptidase IV.
- proteases that are involved in unspecific proteolysis, which ultimately causes the degradation of proteins to amino acids
- regulatory proteases are known that are involved in the functionalization (activation, deactivation, modulation) of endogenous peptide active ingredients [KIRSCHKE, H., LANGNER , J., RIEMANN, S., WIEDERANDERS, B., AN ⁇ SORGE, S. and BOHLEY, P., Lysosomal cysteine proteases. Excerpta Medica (Ciba Foundation Symposium 75), 15 (1980); KR ⁇ USSLICH, H.-G. and WIMMER, E., Viral Proteinases. Ann. Rev. Biochem. 57: 701 (1987)].
- convertases signal peptidases or enkephalinases
- enkephalinases have been discovered in particular in connection with immunological research and neuropeptide research [GOMEZ, S., GLUSCHANKOF, P., LEPAGE, A., MARRAKCHI, N. and COHEN, P. , Proc. Natl. Acad. Be. USA 85, 5468 (1988); ANSORGE, S. and SCH ⁇ N, E., Histochem. 82, 41 (1987)].
- proline determines both the conformation and the stability of these peptides due to its special structure, by protecting against degradation by unspecific proteases [KESSLER, H., Conformation and biological action of cyclic peptides. Appl. Chem. 94, 509 (1982)].
- Enzymes on the other hand, which have a highly specific structure-changing effect on sequences containing proline (HIV protease, cyclophylin, etc.) are attractive targets of current drug research.
- PEP prolin endopeptidase
- DP IV Dipeptidyl peptidase IV
- alanine-containing peptides Similar to the extraordinary proline specificity of these enzymes, their high selectivity for the amino acid alanine is discussed within typical recognition regions in substrates of these enzymes, according to which alanine-containing peptides can adopt similar conformations as structure-analogous proline-containing peptides.
- Such properties of alanine-containing peptide chains have recently been demonstrated by point mutation (exchange of proline for alanine) [DODGE, R.W. and SCHERAGA, H.A., Folding and unfolding kinetics of the proline-to-alanine mutants of bovine pancreatic ribonuclease A. Biochemistry 35 (5) 1548 (1996)].
- DP IV- or DP IV-analogous activity occurs in the bloodstream, where it releases highly specific dipeptides from the N-terminus of biologically active peptides when proline or alanine represent the adjacent residues of the N-terminal amino acid in their sequence. It is therefore assumed that this enzyme is involved in the regulation of polypeptides in vivo [VANHOOF, G., GOOSSENS, F., DE MEESTER, I., HENDRIKS, D. and SCH ⁇ RPE, S., Prolinc motifs and their biological processing , FASEB Journal 9, 736 (1995)].
- the glucose-dependent insulinotropic polypeptides Gastric Inhibitory Polypeptides 1-42 (GIP, .42 ) and Glucagon-Like Peptide Amide-1 7-36 (GLP-1 7. 36 ), hormones that stimulate the glucose-induced insulin secretion of the pancreas (also incretins) are substrates of the DP IV, since they can split off the dipeptides tyrosinyl-alanine or histidyl-alanine from the N-terminal sequences of these peptides in vitro and in situ [MENTLEIN, R., GALLWITZ, B., and SCHMIDT, WE, Dipeptidyl Peptidase IV hydrolyzes gastric inhibitory polypeptide, glucagon-like peptide-1 (7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214, 829 (1993)].
- GIP Gastric Inhibitory Polypeptide
- diabetes mellitus type II is based on reduced insulin secretion or disorders in the receptor function, which are due, among other things, to proteolytically caused concentration anomalies of the incretin [BROWN, 3.C., DAHL, M., KWAWK, S. , MCINTOSH, CHS, OTTE, SC and PEDERSON, RA Peptides 2, 241 (1981); SCHMIDT, WE, SIEGEL, EG, GALLWITZ, B. KÜMMEL, H., EBERT, R. and CREUTZFELDT, W., Characterization of the inulinotropic activity of fragments derived from gastric inhibitory polypeptides.
- proteolytically caused concentration anomalies of the incretin [BROWN, 3.C., DAHL, M., KWAWK, S. , MCINTOSH, CHS, OTTE, SC and PEDERSON, RA Peptides 2, 241 (1981); SCHMIDT, WE, SIEGEL,
- hyperglycaemia and the associated causes or sequelae are treated in various dosage forms by administering insulin (e.g. material isolated from bovine pancreas or genetically derived material) to diseased organisms.
- insulin e.g. material isolated from bovine pancreas or genetically derived material
- All of the previously known, as well as the more modern procedures are characterized by high material costs, high costs and often by decisive impairments of the quality of life of the patients.
- the classic method (daily IV insulin injection, common since the 1930s) treats the acute symptoms of the disease, but leads to prolonged use and a. on severe vascular changes (arteriosclerosis) and nerve damage [LACY, P., Status of Islet Cell Transplantation. Diabetes Care 16 (3) 76 (1993)].
- the aim of the invention is a simple and novel method for lowering the blood glucose level, which according to the invention can be achieved in that the endogenous (or additionally exogenously administered) insulinotropic peptides GIP M2 and GLP are administered causally to an mammalian organism -l 7 .
- Will be degraded is reduced 3f (oa GLP 1 to 7. 37 or its analogues) by DP IV or DP IV-like enzymes, thus reducing the concentration of those Pepdidhormone or its analogues or the siege verzö ⁇ .
- the invention is based on the surprising finding that a reduction in the DP IV- or DP IV-like enzymatic activity acting in the blood circulation has a causal effect on the blood sugar level. It has been found that 1. the reduction of DP IV or DP IV analog activity leads to a relative increase in stability of the glucose-stimulated or externally supplied incretins (or their analogs), i.e. the incretin breakdown in the blood can be controlled by applying effectors of the DP IV or DP IV analog proteins.
- the invention thus relates to the use of effectors of dipeptidyl peptidase VI (DP IV) or DP IV-analogous enzyme activity.
- DP IV dipeptidyl peptidase VI
- DP IV-analogous enzyme activity To lower the blood sugar level below the glucose concentration in the serum of a mammalian organism, which is characteristic of hyperglycaemia.
- the invention relates to the use of effectors of DP IV- or DP IV-analogous enzyme activity in mammals to prevent or alleviate pathological metabolic abnormalities of mammalian organisms selected from glucosuria, hyperlipidemia, metabolic acidosis and diabetes mellitus.
- the invention relates to a method for lowering the blood sugar level below the glucose concentration in the serum of a mammalian organism which is characteristic of hyperglycaemia, which is characterized in that a therapeutically effective amount of an effect of DP is given to a mammalian organism IV or DP IV-analog enzyme activity administered.
- the invention relates to effectors of DP IV or DP IV analog enzyme activity for use in a method for lowering the blood sugar level below the glucose concentration in the serum of a mammalian organism which is characteristic of hyperglycaemia.
- effectors of the DP IV- or DP IV-analogous enzymes applied according to the invention can be used in pharmaceutically usable formulation complexes as inhibitors, substrates, pseudo-substrates, inhibitors of DP IV expression, binding proteins or antibodies of these enzyme proteins or combinations of these different substances, the DP Reduce IV or DP IV analog protein concentration in the mammalian organism.
- Effectors according to the invention are, for example, DP IV inhibitors such as the dipeptide derivatives or dipeptide mimetics alanyl pyrolidide, isoleucyl thiazolidide and the pseudosubstrate N-valyl prolyl, O-benzoyl hydroxylamine.
- the method according to the invention represents a novel approach for lowering increased blood glucose concentration in the serum of mammals. It is simple, commercially usable and suitable for use in therapy, in particular of diseases which are based on above-average blood glucose values, in human medicine.
- the effectors are administered in the form of pharmaceutical preparations containing the active ingredient in combination with customary carrier materials known from the prior art.
- customary carrier materials known from the prior art.
- they are applied parenterally (e.g. IV, in physiological saline) or enterally (e.g. orally, formulated with common carrier materials such as glucose).
- the effectors have to be administered one or more times in order to achieve the desired normalization of the blood glucose values.
- a dose range can be between 1.0 mg and 10.0 mg effector substance per kilogram.
- Example 1 Inhibition of the DP IV -catalyzed hydrolysis of the incretins GIP ⁇ 2 and GLP-I7.se in situ
- incubation of 30 ⁇ M GIP, .42 or 30 ⁇ M GLP-1 7 is achieved in situ.
- Synthetic GIP,. 42 (5 ⁇ M) and synthetic GLP-1 7.
- 36 (15 ⁇ M) were treated with human serum (20%) in 0.1 mM TRICINE buffer at pH 7.6 and 30 ° C.
- Example 2 Inhibition of the degradation of GLP-I ⁇ . ⁇ by the DP IV inhibitor isoleucyl-thiazolidide in vivo.
- Example 3 Modulation of the insulin effect and lowering of the blood glucose level after i. v. Application of the DP IV inhibitor isoleuzyl thiazolidide in vivo.
- Figure 3 illustrates these relationships in the inhibitor-dependent changes in plasma parameters: A - DP IV activity, B - plasma insulin levels, C - blood glucose levels.
- the test group also received an infusion of the inhibitor of 0.75 ⁇ M / min over a test period of 30 minutes (*).
- the control group was infused with an inhibitor-free 0.9% saline solution in the same period.
- the animals were given a glucose dose of lg / kg 40% dextrose solution (w / v).
- Blood samples were taken at ten minute intervals from all test animals. Glucose measurements were performed on whole blood (Lifescan One Touch II analyzer) while the DP IV activity and the insulin concentrations in the plasma were determined.
- the insulin test used here is sensitive between 10 and 160 mU / ml [PEDERSON, R.A., BUCHAN, A.M.J., ZAHEDI-ASH, S., CHEN, C.B. & BROWN, J.C. Reg. Peptides. 3, 53-63 (1982)].
- the DP IV activity was determined spectrophotometrically [DEMUTH, H.-U. and HEINS, J., On the catalytic Mechanism of Dipeptidyl Peptidase IV. in Dipeptidyl Peptides IV (CD 26) in Metabolism and the Immune Response (B. Fleischer, Ed.) R.G. Landes, Biomedical Publishers. Georgetown, 1-35 (1995)]. All measured values are given as mean values with standard deviation.
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
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- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Priority Applications (21)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE59703959T DE59703959D1 (de) | 1996-04-25 | 1997-04-24 | Verwendung von aktivitätsmindernden effektoren der dipeptidyl peptidase iv zur senkung des blutglukosespiegels in säugern |
| KR1020117031497A KR20120014064A (ko) | 1996-04-25 | 1997-04-24 | 포유류에서 혈당을 낮추는데 효과가 있는 이가펩티드성 펩티다제의 활성억제제의 용도 |
| HK99104351.7A HK1019204B (en) | 1996-04-25 | 1997-04-24 | Use of dipeptidyl peptidase iv inhibitors for lowering the blood glucose level in mammals |
| NZ332707A NZ332707A (en) | 1996-04-25 | 1997-04-24 | Use of dipeptidyl peptidase iv inhibitors (dpiv) for lowering the blood glucose level in mammals |
| KR1019980707018A KR100617676B1 (ko) | 1996-04-25 | 1997-04-24 | 포유류에서 혈당을 낮추는 데 효과가 있는 이가펩티드성 펩티다아제의 활성 억제제의 용도 |
| DK97924866T DK0896538T3 (da) | 1996-04-25 | 1997-04-24 | Anvendelse af aktivitetsformindskende effektorer for dipeptidylpeptidase IV til sænkning af blodglucoseniveauet hos pattedyr |
| AU30233/97A AU721477C (en) | 1996-04-25 | 1997-04-24 | The use of dipeptidyl peptidase IV effectors for lowering blood glucose levels in mammals |
| AT97924866T ATE202705T1 (de) | 1996-04-25 | 1997-04-24 | Verwendung von aktivitätsmindernden effektoren der dipeptidyl peptidase iv zur senkung des blutglukosespiegels in säugern |
| CA002252576A CA2252576C (en) | 1996-04-25 | 1997-04-24 | Use of dipeptidyl peptidase iv inhibitors for lowering the blood glucose level in mammals |
| DE122007000083C DE122007000083I1 (de) | 1996-04-25 | 1997-04-24 | Verwendung von aktivitätsmindernden effektoren der dipeptidyl peptidase iv zur senkung des blutglukosespiegels in säuger |
| EP97924866A EP0896538B1 (de) | 1996-04-25 | 1997-04-24 | Verwendung von aktivitätsmindernden effektoren der dipeptidyl peptidase iv zur senkung des blutglukosespiegels in säugern |
| DE200712000038 DE122007000038I1 (de) | 1996-04-25 | 1997-04-24 | Verwendung von Aktivit{tsmindernden Effektoren derDipeptidyl Peptidase IV zur Senkung des Blutglukosespiegels in S{ugern |
| US09/155,833 US6303661B1 (en) | 1996-04-25 | 1997-04-24 | Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals |
| JP53845397A JP2001510442A (ja) | 1996-04-25 | 1997-04-24 | 哺乳動物の血糖値低下のためのジペプチジルペプチダーゼ▲iv▼エフェクターの使用 |
| GR20010401649T GR3036788T3 (en) | 1996-04-25 | 2001-10-03 | Use of dipeptidyl peptidase iv inhibitors for lowering the blood glucose level in mammals |
| LU91334C LU91334I2 (fr) | 1996-04-25 | 2007-04-18 | Sitagliptin, ou un sel de celui-ci pharmaceutiquement acceptable, en particulier le sel phosphate (JANUVIA) |
| NL300280C NL300280I2 (nl) | 1996-04-25 | 2007-04-25 | Toepassing van activiteitsverminderende dipeptidylpeptidase IV-effectoren voor het verlagen van glucosespiegel van het bloed by zoogdieren. |
| NL300308C NL300308I2 (nl) | 1996-04-25 | 2007-12-03 | Toepassing van activiteits verminderende dipeptidylpeptidase |
| LU91382C LU91382I2 (fr) | 1996-04-25 | 2007-12-05 | Vildagliptine ou un de ses sels pharmaceutiquementacceptables - GALVUS |
| US13/458,484 US20130116290A1 (en) | 1996-04-25 | 2012-04-27 | Use of Dipeptidyl Peptidase IV Effectors for Normalizing the Blood Glucose Level in Mammals |
| US15/042,892 US20170007582A1 (en) | 1996-04-25 | 2016-02-12 | Use of Dipeptidyl Peptidase IV Effectors for Normalizing the Blood Glucose Level in Mammals |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19616486.9A DE19616486C5 (de) | 1996-04-25 | 1996-04-25 | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
| DE19616486.9 | 1996-04-25 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/155,833 A-371-Of-International US6303661B1 (en) | 1996-04-25 | 1997-04-24 | Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals |
| US09/932,546 Continuation-In-Part US20020006899A1 (en) | 1996-04-25 | 2001-08-17 | Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997040832A1 true WO1997040832A1 (de) | 1997-11-06 |
Family
ID=7792391
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DE1997/000820 Ceased WO1997040832A1 (de) | 1996-04-25 | 1997-04-24 | Verwendung von dipeptidyl peptidase iv effektoren zur senkung des blutglukosespiegels in säugern |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6303661B1 (https=) |
| EP (3) | EP1084705B1 (https=) |
| JP (3) | JP2001510442A (https=) |
| KR (5) | KR100950722B1 (https=) |
| CN (2) | CN1132578C (https=) |
| AT (1) | ATE202705T1 (https=) |
| AU (1) | AU721477C (https=) |
| CA (1) | CA2252576C (https=) |
| DE (5) | DE19616486C5 (https=) |
| DK (2) | DK0896538T3 (https=) |
| ES (2) | ES2158562T3 (https=) |
| FR (1) | FR14C0089I1 (https=) |
| GR (1) | GR3036788T3 (https=) |
| LT (3) | LTPA2014045I1 (https=) |
| LU (7) | LU91334I2 (https=) |
| NL (2) | NL300280I2 (https=) |
| NZ (1) | NZ332707A (https=) |
| PT (2) | PT896538E (https=) |
| RU (1) | RU2189233C2 (https=) |
| SI (1) | SI1084705T1 (https=) |
| WO (1) | WO1997040832A1 (https=) |
Cited By (123)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999025719A1 (en) * | 1997-11-18 | 1999-05-27 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Novel physiologically active substance sulphostin, process for producing the same, and use thereof |
| WO1999061431A1 (de) * | 1998-05-28 | 1999-12-02 | Probiodrug Gesellschaft für Arzneimittelforschung mbH | Neue effektoren von dipeptidylpeptidase iv |
| WO1999038501A3 (en) * | 1998-02-02 | 2000-01-13 | Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
| EP0995440A1 (de) * | 1998-07-31 | 2000-04-26 | Probiodrug Gesellschaft für Arzneimittelforschung mbH | Verfahren zur Stiegerung des Blutglukosespiegels in Säugern |
| US6303661B1 (en) | 1996-04-25 | 2001-10-16 | Probiodrug | Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals |
| WO2001040180A3 (en) * | 1999-11-30 | 2001-11-08 | Ferring Bv | N-substituted 2-cyanopyrrolidines and their use as antidiabetic agents |
| WO2001062266A3 (en) * | 2000-02-25 | 2002-05-02 | Novo Nordisk As | Use of dpp-iv inhibitors for the treatment of diabetes |
| US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
| WO2002083109A1 (en) * | 2001-04-11 | 2002-10-24 | Ferring Bv | Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase iv |
| US6500804B2 (en) | 2000-03-31 | 2002-12-31 | Probiodrug Ag | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
| WO2003004498A1 (en) * | 2001-07-06 | 2003-01-16 | Merck & Co., Inc. | Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| WO2003015775A1 (en) * | 2001-08-17 | 2003-02-27 | Probiodrug Ag | New dipeptidyl peptidase iv inhibitors and their uses for lowering blood pressure levels |
| WO2003033524A2 (en) | 2001-10-12 | 2003-04-24 | Probiodrug Ag | Peptidyl ketones as inhibitors of dpiv |
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