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WO2001062266A2 - Inhibition de la degenerescence des cellules beta - Google Patents

Inhibition de la degenerescence des cellules beta Download PDF

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Publication number
WO2001062266A2
WO2001062266A2 PCT/DK2001/000115 DK0100115W WO0162266A2 WO 2001062266 A2 WO2001062266 A2 WO 2001062266A2 DK 0100115 W DK0100115 W DK 0100115W WO 0162266 A2 WO0162266 A2 WO 0162266A2
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WO
WIPO (PCT)
Prior art keywords
dpp
inhibitor
use according
diabetes
medicament
Prior art date
Application number
PCT/DK2001/000115
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English (en)
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WO2001062266A3 (fr
Inventor
Richard David Carr
Original Assignee
Novo Nordisk A/S
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Filing date
Publication date
Priority claimed from PCT/DK2001/000045 external-priority patent/WO2001055105A1/fr
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU2001233622A priority Critical patent/AU2001233622A1/en
Priority to EP01905634A priority patent/EP1259246A2/fr
Priority to JP2001561331A priority patent/JP2003523396A/ja
Publication of WO2001062266A2 publication Critical patent/WO2001062266A2/fr
Publication of WO2001062266A3 publication Critical patent/WO2001062266A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2257—Prolactin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • 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 present invention relates to a method for modulating, inhibiting, decreasing, or preventing beta cell degeneration, loss of beta cell function, beta cell dysfunction, and/or death of beta cells, such as necrosis or apoptosis of beta cells in a subject, comprising administering a DPP-IV inhibitor to said subject.
  • the invention furthermore relates to a method for increasing the number and/or the size of beta cells.
  • the invention also relates to a method for delaying the progression of Impaired Glucose Tolerance (IGT) to type 2 diabetes, as well as a method for delaying the progression of non-insulin demanding type 2 diabetes to insulin-demanding type 2 diabetes.
  • ITT Impaired Glucose Tolerance
  • Diabetes is characterized by insufficiency of the pancreatic beta cells to maintain normoglycemia. In type 1 diabetes this is due to destruction of the beta cells by an autoimmune process, whereas in type 2 diabetes it is due to a combination of beta cell deficiency and peripheral insulin resistance.
  • coagulative necrosis This is an abnormal morphological appearance, detected in tissue examined under the microscope.
  • the changes, which affect aggregates of adjacent cells or functionally related cohorts of cells, are seen in a variety of contexts produced by accident, injury, or disease.
  • oxygen deprivation oxygen deprivation
  • hyperthermia hyperthermia
  • immunological attack and exposure to various toxins that inhibit crucial intracellular metabolic processes.
  • Coagulative necrosis is the classical form of cell change seen when tissues autolyze (digest themselves) in vitro.
  • Apoptosis is an active process of cellular self-destruction that is regulated by extrinsic and intrinsic signals occurring during normal development. It is well documented that apoptosis plays a key role in regulation of pancreatic endocrine beta cells. There is increasing evidence that in adult mammalians the beta cell mass is submitted to dynamic changes to adapt insulin production for maintaining euglycemia in particular conditions, such as pregnancy and obesity. The control of beta cell mass depends on a subtle balance between cell proliferation, growth and cell death (apoptosis). A disruption of this balance may lead to impairment of glucose homeostasis.
  • Apoptosis is also associated with diseases such as cancer, immunological disorders, and neurodegenerative disorders.
  • GLP-1 insulinotropic hormone Glucagon like peptide-1
  • the insulinotropic hormone Glucagon like peptide-1 has been shown to stimulate glucose-induced insulin release and insulin biosynthesis and to restore glucose competence.
  • GLP-1 indeed could stimulate beta cell proliferation in vitro.
  • the proliferation was measured as incorporation of the thymidine analogue 5-bromo-2-deoxyuridine into DNA in insulin-positive cells in pancreatic islet cells from newborn rats. GLP-1 was found to increase the number of labelled beta cells.
  • DPP-IV Dipeptidyl peptidase-IV
  • DPP-IV Dipeptidyl peptidase-IV
  • serine protease belonging to the group of post- proline/alanine cleaving amino-dipeptidases specifically removes the two N-terminal amino acids from proteins having proline or alanine in position 2.
  • DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones Glucagon like peptide-1 (GLP-1) and Gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; removal of their two N-terminal amino acids inactivates them.
  • GLP-1 and GIP are active only in their intact forms; removal of their two N-terminal amino acids inactivates them.
  • Published patent application WO 9529691 discloses peptidyl derivates of diesters of alpha-aminoalkylphosphonic acids, particularly those with proline or related structures.
  • Published patent application WO 9819998 discloses N-(N'-substituted glycyl)-2-cyano pyrrolidines, in particular 1-[2-[5-Cyanopyridin-2-yl]amino]-ethylamino]acetyl-2-cyano-(S)- pyrrolidine (NVP-DPP728).
  • Published patent application WO 9925719 discloses sulphostin, a DPP-IV inhibitor prepared by culturing a Streptomyces microorganism.
  • Published patent application WO 9938501 discloses N-substituted 4-8 membered heterocyclic rings.
  • Geman utility models DE 29909208 U, DE 29909210 U, and DE 29909211 U disclose val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and fumar salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.
  • Published patent application WO 9946272 discloses phosphoric compounds as inhibitors of DPP-IV.
  • WO 97/40832 is disclosed use of DPP-IV inhibitors for lowering the blood glucose level in mammals.
  • treatment is understood the management and care of a patient for the purpose of combating the disease, condition, or disorder.
  • beta cell degeneration is intended to mean loss of beta cell function, beta cell dysfunction, and death of beta cells, such as necrosis or apoptosis of beta cells.
  • Impaired Glucose Tolerance is intended to mean a condition indicated by a 2-h postload glucose (2-h PG) between 7.8 mmol/l and 11.1 mmol/l in an Oral Glucose Tolerance Test (OGTT) using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
  • Impaired Fasting Glucose is intended to mean a condition indicated by a Fasting Plasma Glucose (FPG) between 6.1 mmol/l and 7.0 mmol/l, where fasting is defined as no caloric intake for at least 8 hours.
  • non-insulin demanding type 2 diabetes is intended to mean a condition where the individual has insulin resistance, insulin deficiency and either a FPG of more than 7.0 mmol/l or a 2-h PG of more than 11.1 mmol/l when untreated, and where normoglycemia can be achieved without insulin injections.
  • insulin-demanding type 2 diabetes is intended to mean a condition where the individual has insulin resistance, insulin deficiency and either a FPG of more than 7.0 mmol/l or a 2-h PG of more than 11.1 mmol/l when untreated, and where normoglycemia can only be achieved with insulin injections.
  • DPP-IV as used herein is intended to mean Dipeptidyl peptidase IV (EC 3.4.14.5; DPP-IV), also known as CD26. DPP-IV cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline or alanine residue in the penultimate position.
  • DPP-IV inhibitor is intended to indicate a molecule that exhibits inhibition of the enzymatic activity of DPP-IV, such as from 1-100% inhibition, in the assay as described in the section " Methods for measuring the activity of compounds which inhibit the enzymatic activity of CD26/DPP-IV” (see below under experimental).
  • a DPP-IV inhibitor is also intended to comprise active metabolites and prodrugs thereof, such as active metabolites and prodrugs of DPP-IV inhibitors.
  • a “metabolite” is an active derivative of a DPP-IV inhibitor produced when the
  • DPP-IV inhibitor is metabolised.
  • a "prodrug” is a compound that is either metabolised to a
  • DPP-IV inhibitor or is metabolised to the same metabolite(s) as a DPP-IV inhibitor.
  • an analogue is used to designate a peptide wherein one or more amino acid residues of the parent peptide have been substituted by another amino acid residue and/or wherein one or more amino acid residues of the parent peptide have been deleted and/or wherein one or more amino acid residues have been added to the parent peptide.
  • Such addition can take place either in the peptide, at the N-terminal end or at the C- terminal end of the parent peptide, or any combination thereof.
  • derivative is used in the present text to designate a peptide in which one or more of the amino acid residues of the parent peptide have been chemically modified, e.g. by alkylation, acylation, ester formation or amide formation.
  • the present invention relates to use of a DPP-IV inhibitor for the preparation of a medicament for treatment of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells.
  • the present invention relates to use of a DPP-IV inhibitor for the preparation of a medicament for modulation of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells.
  • the present invention relates to use of a DPP-IV inhibitor for the preparation of a medicament for inhibition of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells.
  • the present invention relates to use of a DPP-IV inhibitor for the preparation of a medicament for decreasing beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells. Furthermore, the present invention relates to use of a DPP-IV inhibitor for the preparation of a medicament for reduction of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells.
  • the present invention relates to use of a DPP-IV inhibitor for the preparation of a medicament for arresting beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells.
  • the present invention relates to use of a DPP-IV inhibitor for the preparation of a medicament for prevention of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells.
  • the invention relates to a method for treatment of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells, in a subject comprising administering a DPP-IV inhibitor to said subject.
  • the invention relates to a method for inhibition of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells, in a subject comprising administering a DPP-IV inhibitor to said subject.
  • the invention relates to a method for decreasing beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells, in a subject comprising administering a DPP-IV inhibitor to said subject.
  • the invention relates to a method for reduction of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells, in a subject comprising administering a DPP-IV inhibitor to said subject. Furthermore, the invention relates to a method for arresting beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells, in a subject comprising administering a DPP-IV inhibitor to said subject.
  • the invention also relates to use of a DPP-IV inhibitor for the preparation of a medicament for increasing the number of beta cells.
  • the invention also relates to use of a DPP-IV inhibitor for the preparation of a medicament for increasing the size of beta cells.
  • the invention furthermore relates to use of a DPP-IV inhibitor for the preparation of a medicament for delaying the progression of Impaired Fasting Glucose (IFG) to type 2 diabetes.
  • IGF Impaired Fasting Glucose
  • the invention furthermore relates to use of a DPP-IV inhibitor for the preparation of a medicament for delaying the progression of non-insulin demanding type 2 diabetes to insulin- demanding type 2 diabetes.
  • the invention also relates to a method of increasing the number of beta cells in a subject comprising administering a DPP-IV inhibitor to said subject.
  • the invention also relates to a method of increasing the number and the size of beta cells in a subject comprising administering a DPP-IV inhibitor to said subject.
  • the invention furthermore relates to a method of delaying the progression of Impaired
  • Glucose Tolerance to type 2 diabetes in a subject comprising administering a DPP-IV inhibitor to said subject.
  • the invention furthermore relates to a method of delaying the progression of non- insulin demanding type 2 diabetes to insulin-demanding type 2 diabetes in a subject comprising administering a DPP-IV inhibitor to said subject.
  • the invention also relates to the use according to any of the above uses in a regimen which additionally comprises treatment with human growth hormone, a growth hormone releasing agent or a growth factor such as prolactin or placental lactogen; the use of human growth hormone, a growth hormone releasing agent or a growth factor such as prolactin or placental lactogen for the preparation of a medicament for inhibiting the beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells in a subject; the use of human growth hormone, a growth hormone releasing agent or a growth factor such as prolactin or placental lactogen for the preparation of a medicament for treatment of beta cell degeneration, such as necrosis or apoptosis of ⁇ -cells in a subject.
  • the DPP-IV inhibitor is selected from peptides, polypeptides, proteins, enzymes, antibodies as well as non-peptides, e.g. a small organic molecule; each of which constitutes individual embodiments
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral, in particular oral.
  • compositions (or medicaments) containing a DPP-IV inhibitor may be administered parenterally to patients in need of such a treatment.
  • Parenteral administration may be performed by subcutaneous, intramuscular or intravenous injection by means of a syringe, optionally a pen-like syringe.
  • parenteral administration can be performed by means of an infusion pump.
  • a further option is a composition that may be a powder or a liquid for the administration of the DPP-IV inhibitor in the form of a nasal or pulmonal spray.
  • the DPP-IV inhibitor can also be administered transdermally, e.g. from a patch, optionally a iontophoretic patch, or transmucosally, e.g. bucally.
  • the DPP-IV inhibitor can also be administered transdermally, e.g. from a patch, optionally a iontophoretic patch, or transmucosally, e.g. bucally.
  • the DPP-IV inhibitor can
  • DPP-IV inhibitor can also be administered by gene therapy, such as by implanting a cell line transformed with a vector such that it secretes the DPP-IV inhibitor.
  • the implanted cells may be encapsulated in semi permeable membranes, e.g. macro- or microencapsulated.
  • solutions containing a DPP-IV inhibitor may also contain a surfactant in order to improve the solubility and/or the stability of the DPP-IV inhibitor.
  • DPP-IV inhibitor to be used and the optimal dose level for any patient will depend on the disease to be treated and on a variety of factors including the efficacy of the specific peptide derivative employed, the age, body weight, physical activity, and diet of the patient, on a possible combination with other drugs, and on the severity of the case. It is recommended that the dosage of the DPP-IV inhibitor be determined for each individual patient by those skilled in the art.
  • Figure 1 shows BrdU in remnant pancreas of rats 8 days after a 60 % pancreatectomy and after 4 days of treatment with Val-Pyr.
  • Figure 2 shows BrdU in regenerating pancreas of rats 8 days after a 60 % pancreatectomy and after 4 days of treatment with Val-Pyr.
  • Figure 5 shows absence of insulin in regenerating pancreas of rats 8 days after a 60 % pancreatectomy and after 4 days of treatment with vehicle.
  • CD26/DPP-IV is tested for their ability to inhibit the enzyme activity of purified CD26/DPP-IV. Briefly, the activity of CD26/DPP-IV is measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNA by DPP-IV liberates the product p-nitroanilide (pNA), whose rate of appearance is directly proportional to the enzyme activity. Inhibition of the enzyme activity by specific enzyme inhibitors slows down the generation of pNA. Stronger interaction between an inhibitor and the enzyme results in a slower rate of generation of pNA. Thus, the degree of inhibition of the rate of accumulation of pNA is a direct measure of the strength of enzyme inhibition. The accumulation of pNA is measured spectrophotometrically. The inhibition constant, Ki, for each compound is determined by incubating fixed amounts of enzyme with several different concentrations of inhibitor and substrate.
  • Ki The inhibition constant, Ki, for each compound is determined by
  • Assay buffer 50 mM Tris pH7.4, 150 mM NaCI, 0,1% Triton X-100.
  • Apoptosis and inhibition thereof can be detected in the following way:
  • the free 3' OH strand breaks resulting from DNA degradation which is associated with apoptosis can be detected with the terminal deoxynucleotidyl transferase-mediated dUTP-X3' nick end-labeling (TUNEL) technique (J Cell Biol 199: 493, 1992) or using the following kits e.g. In Situ Cell Death Detection kit; Boehringer Mannheim, Mannheim or ApoTag, Oncor, Gaithersburg, MD).
  • TUNEL terminal deoxynucleotidyl transferase-mediated dUTP-X3' nick end-labeling
  • kits e.g. In Situ Cell Death Detection kit; Boehringer Mannheim, Mannheim or ApoTag, Oncor, Gaithersburg, MD.
  • Preparation of pancreatic sections or islet cultures for apoptosis staining using the TUNEL technique is described in (Dia
  • apoptosis can be detected by double staining of cultured beta cells/islets with the DNA binding dyes Hoechst 33342 and propidium iodide as described in (Diabetologia 42: 55, 1999 and J. Clin.lnvest. 98(7): 1568-1574, 1996).
  • a 60% pancreatectomy was performed on a total of 12 male Sprague-Dawley rats. Vehicle and the DPP-IV inhibitor Val-Pyr was administered to 6 of these from day 4 to 8 in a dose of 20 mg/kg p.o. x2, while the remaining 6 rats were treated with vehicle alone.
  • Table 1 Qualitative evaluation of remnant and regenerated pancreatic tissue stained for insulin and BrdU

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  • General Health & Medical Sciences (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

La présente invention concerne un procédé pour empêcher la dégénérescence des cellules bêta, par exemple, la nécrose ou l'apoptose des cellules bêta chez un sujet; le procédé consiste à administrer à l'individu un inhibiteur de DPP-IV. L'invention concerne en outre un procédé pour augmenter le nombre et/ou la taille des cellules bêta. Elle se rapporte également à un procédé pour freiner la progression de l'intolérance au glucose vers le diabète de type 2 ainsi qu'un procédé pour retarder la progression du diabète de type 2 non insulino-dépendant vers le diabète de type 2 insulino-dépendant.
PCT/DK2001/000115 2000-02-25 2001-02-20 Inhibition de la degenerescence des cellules beta WO2001062266A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2001233622A AU2001233622A1 (en) 2000-02-25 2001-02-20 Inhibition of beta cell degeneration
EP01905634A EP1259246A2 (fr) 2000-02-25 2001-02-20 Inhibition de la degenerescence des cellules beta
JP2001561331A JP2003523396A (ja) 2000-02-25 2001-02-20 ベータ細胞変性の抑制

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DKPA200000295 2000-02-25
DKPA200000295 2000-02-25
DKPA200000983 2000-06-23
DKPA200000983 2000-06-23
PCT/DK2001/000045 WO2001055105A1 (fr) 2000-01-24 2001-01-22 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv
DKPCT/DK01/00045 2001-01-22

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WO2001062266A2 true WO2001062266A2 (fr) 2001-08-30
WO2001062266A3 WO2001062266A3 (fr) 2002-05-02

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Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6500804B2 (en) 2000-03-31 2002-12-31 Probiodrug Ag Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US6548481B1 (en) 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US6559314B2 (en) 1999-06-10 2003-05-06 Probiodrug Ag Method for the production of thiazolidin
WO2003037327A1 (fr) * 2001-10-26 2003-05-08 F. Hoffmann-La-Roche Ag Derives de pyrrolidine n-substitues en tant qu'inhibiteurs de la dipeptidyl peptidase iv
WO2004007446A1 (fr) * 2002-07-10 2004-01-22 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive de l'azetidine ou ses sels
EP1465891A2 (fr) * 2001-12-26 2004-10-13 Guilford Pharmaceuticals Inc. Inhibiteurs de la dipeptidyl peptidase iv
US6844316B2 (en) 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
EP1537880A1 (fr) 2002-09-11 2005-06-08 Takeda Pharmaceutical Company Limited Preparation a liberation prolongee
US6946480B2 (en) 2002-02-28 2005-09-20 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
US6949515B2 (en) 1999-08-24 2005-09-27 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US7053055B2 (en) 1998-06-24 2006-05-30 Prosidion Ltd. Compounds of unstable DP IV-inhibitors
US7084120B2 (en) 1998-06-24 2006-08-01 Probiodrug Ag Prodrugs of DP IV-inhibitors
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7122555B2 (en) 2003-06-20 2006-10-17 Hoffmann-La Roche Inc. Pyrido [2,1-a] isoquinoline derivatives
US7132104B1 (en) 2000-10-27 2006-11-07 Probiodrug Ag Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
US7132443B2 (en) 2001-06-27 2006-11-07 Smithklinebeecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
US7183290B2 (en) 2001-06-27 2007-02-27 Smithkline Beecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
US7196201B2 (en) 2001-06-27 2007-03-27 Smithkline Beecham Corporation Pyrrolidines as dipeptidyl peptidase inhibitors
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US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
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US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
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EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8003636B2 (en) 2007-11-13 2011-08-23 Sanofi-Aventis Deutschland Gmbh Certain crystalline diphenylazetidinone hydrates, pharmaceutical compositions thereof and methods for their use
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US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US8143427B2 (en) 2007-03-22 2012-03-27 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
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US7132104B1 (en) 2000-10-27 2006-11-07 Probiodrug Ag Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
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US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
US7196201B2 (en) 2001-06-27 2007-03-27 Smithkline Beecham Corporation Pyrrolidines as dipeptidyl peptidase inhibitors
US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
US7368576B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7183290B2 (en) 2001-06-27 2007-02-27 Smithkline Beecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
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US7314884B2 (en) 2001-10-26 2008-01-01 Hoffmann-La Roche Inc. DPP IV inhibitors
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EP1465891A2 (fr) * 2001-12-26 2004-10-13 Guilford Pharmaceuticals Inc. Inhibiteurs de la dipeptidyl peptidase iv
US6946480B2 (en) 2002-02-28 2005-09-20 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
WO2004007446A1 (fr) * 2002-07-10 2004-01-22 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive de l'azetidine ou ses sels
EP1537880A1 (fr) 2002-09-11 2005-06-08 Takeda Pharmaceutical Company Limited Preparation a liberation prolongee
US7205290B2 (en) 2003-04-01 2007-04-17 Sanofi-Aventis Deutschland Gmbh Diphenylazetidinone with improved physiological properties, process for its preparation, medicaments comprising this compound, and its use
US7772429B2 (en) 2003-04-01 2010-08-10 Sanofi-Aventis Deutschland Gmbh Diphenylazetidinone with improved physiological properties, process for its preparation, medicaments comprising this compound, and its use
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
US7638638B2 (en) 2003-05-14 2009-12-29 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7718666B2 (en) 2003-06-20 2010-05-18 Hoffmann-La Roche Inc. Pyrido [2,1-a] isoquinoline derivatives
US7122555B2 (en) 2003-06-20 2006-10-17 Hoffmann-La Roche Inc. Pyrido [2,1-a] isoquinoline derivatives
US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US8143427B2 (en) 2007-03-22 2012-03-27 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative
US8003636B2 (en) 2007-11-13 2011-08-23 Sanofi-Aventis Deutschland Gmbh Certain crystalline diphenylazetidinone hydrates, pharmaceutical compositions thereof and methods for their use

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