DK2547355T3 - Tfpi-inhibitorer og fremgangsmåder til anvendelse - Google Patents

Tfpi-inhibitorer og fremgangsmåder til anvendelse Download PDF

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DK2547355T3
DK2547355T3 DK11756689.3T DK11756689T DK2547355T3 DK 2547355 T3 DK2547355 T3 DK 2547355T3 DK 11756689 T DK11756689 T DK 11756689T DK 2547355 T3 DK2547355 T3 DK 2547355T3
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peptide
tfpi
amino acid
binding
group
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DK11756689.3T
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Ulrich Reineke
Frank Osterkamp
Thomas Polakowski
Michael Dockal
Rudolf Hartmann
Markus Fries
Friedrich Scheiflinger
Hartmut Ehrlich
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Baxalta GmbH
Baxalta Inc
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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8114—Kunitz type inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional [2D] or three-dimensional [3D] molecular structures, e.g. structural or functional relations or structure alignment
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • G16B20/30—Detection of binding sites or motifs
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • G16B20/50—Mutagenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/745—Assays involving non-enzymic blood coagulation factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/81—Protease inhibitors
    • G01N2333/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • G01N2333/811—Serine protease (E.C. 3.4.21) inhibitors
    • G01N2333/8114—Kunitz type inhibitors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
    • G01N2333/96444—Factor X (3.4.21.6)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
    • G01N2333/96447—Factor VII (3.4.21.21)
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/02—Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
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    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N2500/20—Screening for compounds of potential therapeutic value cell-free systems

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  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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Claims (13)

1. Peptid der binder Tissue Factor Pathway Inhibitor-la (TFPI-la), omfattende strukturen med formel (XI): X4001-Q-X4003-X4004-X4005-X4006-X4007-X4008-X4009-X4010-X4011 -X4012-X4013-X4014-R-X4016-X4017-X4018-X4019-X4020 (XI), hvor X4001 er F; hvor X4003 er S; hvor X4004 er K,; hvor X4005 er p; hvor X4006 er N eller S; hvor X4007 er V; hvor X4008 er H; hvor X4009 er Tle; hvor X4010 er D; hvor X4011 er a eller G; hvor X4012 er Y; hvor X4013 er F; hvor X4014 er E; hvor X4016 er L eller Hle; hvor X4017 er en aminosyre valgt fra gruppen bestående af Aib, Hie, Deg, Eca, og Aic; hvor X4018 er A; hvor X4019 er K; og hvor X4020 er L.
2. Peptidet ifølge krav 1, hvor peptidet består af aminosyresekvensen valgt fra gruppen bestående af SEQ ID NO: 4133, 4137, 4153-4155, og 4158.
3. Peptid der binder Tissue Factor Pathway Inhibitor-la (TFPI-la), omfattende en aminosyresekvens med mindst 90% identitet med aminosyresekvensen valgt fra gruppen bestående af SEQ ID NO: 4133, 4137, og 4153-4155.
4. Peptidet ifølge krav 3, hvor peptidet omfatter mindst 90% identitet med sekvensen af SEQ ID NO: 4133.
5. Peptidet ifølge krav 3, hvor peptidet omfatter en aminosyresekvens valgt fra gruppen bestående af SEQ ID NO: 4133, 4137, og 4153-4155.
6. Peptid ifølge krav 1 eller krav 2 yderligere omfattende N-terminale aminosyre(r) og/eller molekyldele bundet til X4001 og valgt fra gruppen bestående af FAM-Ttds, PE, Palm, 2-phenylacetyl, 3-phenylpropionyl, 2-(naphtha-2-yl) acetyl, hexanoyl, 2-methylpropionyl, 3-methylbutanoyl, 2-naphthylsulfonyl, og 1-naphthylsulfonyl.
7. Peptid ifølge krav 1, krav 2, eller krav 6 yderligere omfattende X4021 bundet til X4020, hvor X4021 omfatter C-terminale aminosyre(r) og/eller molekyldele valgt fra gruppen bestående af C, c, C(NEM), K(Ttds-maleimidopropionyl(EtSH)), 3-[2-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-propionsyre, 3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionsyre, 3-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-propionsyre, [2-(2-amino-ethoxy)-ethoxy]-eddikesyre, K(Tdts-maleimid), K(AOA), og Cea.
8. Peptidet ifølge et hvilket som helst af kravene 1-5, hvor peptidet inhiberer Tissue Factor Pathway Inhibitor-la (TFPI-la)-aktivitet og binder til TFPI-la med en dissociationskonstant på mindre end 10 μΜ.
9. Peptidet ifølge et hvilket som helst af kravene 1-8, hvor peptidet er konjugeret til en polyethylenglycol (PEG)-molekyldel, humant serumalbumin (HSA), et antistof eller fragment deraf, hydroxyethylstivelse, en prolin-alanin-serin-multimer (PASylation), en C12-C18 fedtsyre, eller polysialinsyre.
10. Tissue Factor Pathway Inhibitor-la (TFPI-la)-bindende peptid omfattende en homo-dimer eller homo-multimer af to eller flere peptider ifølge krav 1 eller krav 2 eller krav 3 eller krav 4 eller krav 5.
11. TFPI-bindende peptid omfattende en hetero-dimer eller hetero-multimer af to eller flere peptider ifølge krav 1 eller krav 2 eller krav 3 eller krav 4 eller krav 5.
12. Peptidet ifølge et hvilket som helst af kravene 1-11 til anvendelse i behandling af et individ der lider af en blødersygdom eller har risiko for at lide af en blødersygdom forårsaget af mangelfuld blodkoagulationsfaktoraktivitet eller mangelfuld blodpladeaktivitet.
13. Anvendelse af peptidet ifølge et hvilket som helst af kravene 1-11 i fremstillingen af et medikament til behandlingen af et individ der lider af en blødersygdom eller har risiko for at lide af en blødersygdom forårsaget af mangelfuld blodkoagulationsfaktoraktivitet eller mangelfuld blodpladeaktivitet.
DK11756689.3T 2010-03-19 2011-02-11 Tfpi-inhibitorer og fremgangsmåder til anvendelse DK2547355T3 (da)

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US31575810P 2010-03-19 2010-03-19
PCT/US2011/024604 WO2011115712A2 (en) 2010-03-19 2011-02-11 Tfpi inhibitors and methods of use

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US (5) US8450275B2 (da)
EP (2) EP2547355B1 (da)
JP (3) JP5730983B2 (da)
KR (2) KR101784030B1 (da)
CN (2) CN103025345B (da)
AU (1) AU2011227714B2 (da)
BR (1) BR112012023559A2 (da)
CA (1) CA2793465C (da)
DK (1) DK2547355T3 (da)
ES (2) ES2621809T3 (da)
NZ (3) NZ603028A (da)
WO (1) WO2011115712A2 (da)

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