WO2010118435A2 - Par-1 activation by metalloproteinase-1 (mmp-1) - Google Patents

Par-1 activation by metalloproteinase-1 (mmp-1) Download PDF

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Publication number
WO2010118435A2
WO2010118435A2 PCT/US2010/030783 US2010030783W WO2010118435A2 WO 2010118435 A2 WO2010118435 A2 WO 2010118435A2 US 2010030783 W US2010030783 W US 2010030783W WO 2010118435 A2 WO2010118435 A2 WO 2010118435A2
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par
mmp
agent
patient
platelet
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English (en)
French (fr)
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WO2010118435A3 (en
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Athan Kuliopulos
Georgios Koukos
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Tufts Medical Center Inc
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Tufts Medical Center Inc
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Priority to CA2758322A priority Critical patent/CA2758322C/en
Priority to PCT/US2010/030783 priority patent/WO2010118435A2/en
Priority to EP10762578.2A priority patent/EP2416799B1/en
Priority to US13/263,715 priority patent/US20120121706A1/en
Priority to AU2010233089A priority patent/AU2010233089B2/en
Priority to JP2012504929A priority patent/JP2012523438A/ja
Application filed by Tufts Medical Center Inc filed Critical Tufts Medical Center Inc
Publication of WO2010118435A2 publication Critical patent/WO2010118435A2/en
Publication of WO2010118435A3 publication Critical patent/WO2010118435A3/en
Anticipated expiration legal-status Critical
Priority to US14/460,353 priority patent/US9376499B2/en
Priority to US15/165,988 priority patent/US20170065668A1/en
Ceased legal-status Critical Current

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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
    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/005—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters containing a biologically active substance, e.g. a medicament or a biocide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/436—Inhibitors, antagonists of receptors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the agent may be administered after an angioplasty procedure, a coronary bypass procedure, or an open-heart surgery has been performed on the patient but preferably for no more than two weeks.
  • the agent comprises SCH 530348.
  • FIG.2G shows the cleavage of PAR1 N-terminal extracellular domain mutants expressed on COS7
  • FIG.2H shows the cleavage of wild-type PAR-2 expressed on COS7 Cells by MMP-1 or trypsin.
  • FIG.4D shows MMP-1 induces platelet aggregation.
  • FIG.5A shows the effect of pharmacologic blockage of metalloproteases or PAR1 on platelet aggregation in the presence of 5mg/ml collagen.
  • FIG.5C shows the effect of pharmacologic blockage of metaJloproteases or PAR1 on platelet Rho-GTP activity in the presence of 5mg/ml collagen.
  • FIG. ⁇ D shows the effect of various blocking Abs (a ⁇ ti- MMP-1, anti-MMP-8 and anti- MMP-13) and various inhibitors (ARC (P2Y12 antagonist AR-C69931MX), ASA (aspirin)) on platelet Rho-GTP activity in the presence of 5mg/ml oolagen alone or together with MMP-1 (Calbiochem or S2, BioMol).
  • ARC P2Y12 antagonist AR-C69931MX
  • ASA aspirin
  • FIGs. 6A-6B show that inhibition of MMP-1 or PAR1 prevents early micro-thrombus formation on collagen surfaces in the presence of heparin.
  • FIG.6H shows the detection of MMP-1 activity in guinea pig platelet supernatant and arterial dot induced by collagen.
  • FIG.7C shows the effect of pharmacologic blockage of metalloproteases or PAR1 on guinea pig platelet aggregation in the presence of 10 mg/ml collagen.
  • an "agonist” refers to any natural or synthetic molecule or combination of molecules that increases a biological activity by at least or at least about 2 fold, about 3 fold, about 4 fold, about 5 fold, about 7 fold, about 10 fold, about 20 fold, about 50 fold or about 100 fold or more in a standard bioassay or in vivo or when used in a therapeutically effective dose.
  • an "agonisf” refers to any natural or synthetic molecule or combination of molecules that activates MMP-1 mediated PAR-1 signaling.
  • Matrix metalloproteinase-1 (MMP-1, aliases: CLG, CLGN, EC 3.4.247) is also known as fibroblast collagenase, interstitial collagenase, matrix metallopeptidase-1 or matrix metalloprotease-1 (HGNC: 71561; Entrez Gene: 43122; UniProtKB: P039563; Ensembl: ENSG000001966117; GenBank Accession Number NMJ)02421).
  • the MMP-1 gene encodes a secreted enzyme that can break down interstitial collagens, types I, II, and III. The gene is part of a duster of MMP genes, which localize to human chromosome 11q22.3.
  • Matrix metalloprotease-2 (MMP-2; aliases: CLG4, CLG4A, EC 3.4.24.24, MMP-II, MONA,
  • MMP- 1, MMP-2. etc. are referred to numerically as MMP- 1, MMP-2. etc. as well as by a common name.
  • the MMPs share several structural and functional properties but differ in their substrate specificities. There are at least 25 members of the MMP family, categorized based on their domain structures and their preferences for macromolecular substrates (Nelson. A. et at., (2000) J. Clin. Oncol. 18, 1135-1149., Woessner, J. F., and Nagase, H. (2000) Matrix Metalloproteinases and TIMPs, Oxford University Press, Oxford).
  • peptide or "polypeptide” is intended to encompass a single amino acid sequence
  • thrombin-dependant activation of PAR-V refers to the activation of PAR-1 signaling by a serine protease (such as thrombin or plasmin or APC) that cleaves the N terminus of PAR-1 between the arginine residue at position 41, and the serine residue at position 42.
  • FIG. 4B the ability of MMP-1 to induce platelet shape change was determined. Washed human platelets were pretreated with 2 mM EGTA and then challenged with MMP-1 in the presence or absence of 1 ⁇ M RWJ-56110 while stirring at 1100 rpm. Shape change was measured as described above.
  • Collagen zymography revealed that the platelet-rich clot isolated from injured carotid arteries of vehicle-treated animals (veh clot) had significant MMP-1 activity, which co-migra1ed with APMA-activated MMP-1 and with the MMP-1 activity from the supernatants of collagen-activated platelets (FIG, 6H). Conversely, resting platelets (control) from whole blood or arterial thrombi from animals treated with the MMP1-inhibitor (FN439 clot) did not contain active MMP-1. These data, together with the previous results, indicate that inhibition of MMP1-PAR1 may provide substantial protection against collagen-dependent platelet activation and acute arterial thrombosis in animals.
  • Anti-phospho p38MAPK, p38MAPK, anti-phospho-MAPKAP-K2, and anti-MAPKAP-K2 were from Cell Signaling, anti-RhoA (clone 26C4) was from Santa Cruz Biotechnology.
  • Com trypsin inhibitor and thrombin were from Haematologic Technologies, the Quick Change
  • an agent acts as a direct or indirect antagonist of the MMP- 1 ⁇ PAR-1 signaling pathway.
  • Direct antagonists are compounds that bind directly to their target molecule, such as MMP-1 or PAR-1, and inhibit the biological activity of that target molecule.
  • a selected nucleic add e.g., a coding sequence
  • a sequence element e.g., a promoter and/or ribosome binding site (Shine-Dalgarno sequence)
  • sequence elements can be controlled such that transcription and/or translation of the selected nucleic acid can be selectively induced.
  • sequence elements include inducible promoters such as tac, T7, P(BAD) (araBAD), and beta-D-glucuronidase (uidA) promoter- based vectors.
  • the non-immobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed (e.g., by washing) under conditions such that any complexes formed will remain immobilized on the solid surface.
  • the detection of complexes anchored on the solid surface can be accomplished in a number of ways. Where the previously non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed.
  • the invention further contemplates other peptide antagonists that interfere with collagen induced platelet activation and may be combined with the herein-described agents that modulate the MMP- 1 mediated cleavage of PAR-1 between aspartic add at position 39 (D39) and proline at position 40 (P40) of said patienfs protease-activated reoeptor-1 (PAR-1).
  • MMP peptide inhibitors based on synthetic triple-helical peptides (THPs) are described in U.S. Patent Application No. 2008/0125354.
  • PAR-1 antibody or peptide antagonists are described in the PCT application WO 2008/011107. The contents of these patent documents are hereby incorporated herein by reference in their entirety.
  • tetracydine derivatives that may be tested for inhibitory activity on the MMP-1 mediated PAR-1 signaling pathway include, but are not limited to, Chlortetracycline, Oxytetracycline, Demeclocydine, Doxycycjine, Lymecycline, Meclocydine, Methacyciine, Minocycline, Rolitetracycline and Tigecycline.
  • Non- limiting examples of tetracycline derivatives have been described in U.S. Pat. No.2,980,584; U.S. Pat No. 2,990,331; U.S. Pat. No.3,062,717; U.S. Pat No. 3,165,531; U.S. Pat. No.
  • the present invention also provides unit dose formulations comprising two or more antithrombotic agents, wherein each thrombotic "agent" is present in a therapeutically effective amount when administered in the combination.
  • the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

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PCT/US2010/030783 2009-04-10 2010-04-12 Par-1 activation by metalloproteinase-1 (mmp-1) Ceased WO2010118435A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
PCT/US2010/030783 WO2010118435A2 (en) 2009-04-10 2010-04-12 Par-1 activation by metalloproteinase-1 (mmp-1)
EP10762578.2A EP2416799B1 (en) 2009-04-10 2010-04-12 Par-1 activation by metalloproteinase-1 (mmp-1)
US13/263,715 US20120121706A1 (en) 2009-04-10 2010-04-12 PAR-1 Activation by Metalloproteinase-1 (MMP-1)
AU2010233089A AU2010233089B2 (en) 2009-04-10 2010-04-12 Par-1 activation by metalloproteinase-1 (MMP-1)
JP2012504929A JP2012523438A (ja) 2009-04-10 2010-04-12 メタロプロテイナーゼ−１（ｍｍｐ−１）によるｐａｒ−１活性化
CA2758322A CA2758322C (en) 2009-04-10 2010-04-12 Par-1 activation by metalloproteinase-1 (mmp-1)
US14/460,353 US9376499B2 (en) 2009-04-10 2014-08-14 PAR-1 activation by metalloproteinase-1 (MMP-1)
US15/165,988 US20170065668A1 (en) 2009-04-10 2016-05-26 PAR-1 Activation by Metalloproteinase-1 (MMP-1)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US16835309P 2009-04-10 2009-04-10
US16836009P 2009-04-10 2009-04-10
US61/168,353 2009-04-10
US61/168,360 2009-04-10
PCT/US2010/030783 WO2010118435A2 (en) 2009-04-10 2010-04-12 Par-1 activation by metalloproteinase-1 (mmp-1)

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US13/263,715 A-371-Of-International US20120121706A1 (en) 2009-04-10 2010-04-12 PAR-1 Activation by Metalloproteinase-1 (MMP-1)
US14/460,353 Continuation US9376499B2 (en) 2009-04-10 2014-08-14 PAR-1 activation by metalloproteinase-1 (MMP-1)

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Cited By (9)

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WO2012118498A1 (en) * 2011-03-02 2012-09-07 Aquilus Pharmaceuticals, Inc. Compounds and methods for the treatment of pain and other disorders
WO2012090207A3 (en) * 2010-12-30 2012-10-04 Hadasit Medical Research Services & Development Limited Par1 and par2 c-tail peptides and peptide mimetics
WO2012139137A3 (en) * 2011-04-08 2012-12-27 Tufts Medical Center, Inc. Pepducin design and use
WO2013092860A3 (en) * 2011-12-20 2013-12-05 Angioclinic Ag Hyaluronic acid and its use for treating venous insufficiency and varicose veins
WO2013183725A1 (ja) * 2012-06-06 2013-12-12 国立大学法人九州大学 非ヒトモデル動物、非ヒトモデル動物の作製方法及び抗血栓薬のスクリーニング方法
WO2015107139A1 (en) * 2014-01-17 2015-07-23 Proyecto De Biomedicina Cima, S.L. Compounds for use as antifibrinolytic agents
CN106551944A (zh) * 2015-09-25 2017-04-05 南开大学 四环素类衍生物作为par-1抑制剂的用途
CN111788300A (zh) * 2017-12-28 2020-10-16 株式会社钟化 细胞聚集抑制剂
US11712483B2 (en) * 2013-03-14 2023-08-01 The Regents Of The University Of California Activatable membrane-interacting peptides and methods of use

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CN111548418A (zh) 2012-02-15 2020-08-18 比奥贝拉蒂治疗公司 因子viii组合物及其制备和使用方法
WO2013123457A1 (en) 2012-02-15 2013-08-22 Biogen Idec Ma Inc. Recombinant factor viii proteins
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US9376499B2 (en) 2016-06-28
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AU2010233089B2 (en) 2016-05-26
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EP2416799B1 (en) 2017-11-01
CA2758322A1 (en) 2010-10-14
US20150023975A1 (en) 2015-01-22
JP2012523438A (ja) 2012-10-04
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