[go: up one dir, main page]

WO2014139014A1 - Méthodes et compositions pour l'inhibition de l'activité du facteur de croissance de l'endothélium vasculaire et de la perméabilité vasculaire - Google Patents

Méthodes et compositions pour l'inhibition de l'activité du facteur de croissance de l'endothélium vasculaire et de la perméabilité vasculaire Download PDF

Info

Publication number
WO2014139014A1
WO2014139014A1 PCT/CA2014/050261 CA2014050261W WO2014139014A1 WO 2014139014 A1 WO2014139014 A1 WO 2014139014A1 CA 2014050261 W CA2014050261 W CA 2014050261W WO 2014139014 A1 WO2014139014 A1 WO 2014139014A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxo
carboxamide
indole
hexahydroazepino
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2014/050261
Other languages
English (en)
Inventor
Alon HENDEL
David J. Granville
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of British Columbia
Original Assignee
University of British Columbia
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of British Columbia filed Critical University of British Columbia
Publication of WO2014139014A1 publication Critical patent/WO2014139014A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/40—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
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • 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
    • 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

  • VEGF ECM-sequestered VEGF can be liberated by proteases and this process has significant implications on vascular integrity.
  • VEGF binds to the growth factor binding domain in fibronectin (Wijelath et al, Circ. Res. 91 :25-31, 2002; Wijelath et al, Circ. Res. 99:853-860, 2006; Martino et al, Sci. Transl. Med. 3:100ra89, 2011).
  • GzmB inhibitors are known to a person of skill in the art and are, for example, described in international patent application published under WO 2012/076985, WO 2003/065987 and United States patent application published under US 2003/0148511 ; Willoughby et al, Bioorg. Med. Chem. Lett. 12:2197-2200, 2002; Hill et al., J. Thorac. Cardiovasc. Surg. 110: 1658-1662, 1995; Sun et al, J. Biol. Chem. 271 :27802-27809, 1996; Sun et al, J. Biol. Chem. 272:15434-15441, 1997; Bird et al, Mol. Cell Biol.
  • An inhibiting or interfering nucleic acid thus refers to a single-stranded nucleic acid molecule that is complementary to a target mRNA sequence or to the double-stranded RNA formed by two complementary strands or by a single, self-complementary strand.
  • An inhibiting or interfering nucleic acid can have substantial or complete identity to the target gene or sequence, or can comprise a region of mismatch (i.e., a mismatch motif).
  • a GzmB inhibitor for use in the compositions, methods and uses of the disclosure is an inhibitory polypeptide or a peptide.
  • the subject polypeptides or peptides can also be modified by attachment to other compounds for the purposes of incorporation into carrier molecules, changing polypeptide or peptide bioavailability, extending or shortening half -life, controlling distribution to various tissues or the blood stream, diminishing or enhancing binding to blood components, and the like.
  • the prior examples serve as examples and are non- limiting.
  • Compounds or pharmaceutical compositions in accordance with this invention or for use in the methods disclosed herein can be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, and the like.
  • a medical device or appliance such as an implant, graft, prosthesis, stent, and the like.
  • implants can be devised which are intended to contain and release such compounds or compositions.
  • An example would be an implant made of a polymeric material adapted to release the compound over a period of time.
  • the Granzyme B inhibitor also can be administered in the form of sustained-release formulations (see, e.g., US5, 378,475) comprising, for example, gelatin, chondroitin sulfate, a polyphosphoester, such as bis-2-hydroxyethyl-terephthalate (BHET), or a polylactic-glycolic acid.
  • sustained-release formulations see, e.g., US5, 378,475
  • chondroitin sulfate a polyphosphoester, such as bis-2-hydroxyethyl-terephthalate (BHET), or a polylactic-glycolic acid.
  • GzmB can cleave both plasma and cell derived FN. Since the endogenous cellular matrix is more complex and may contain other pericellular matrix proteins that can bind VEGF (Yoo et al, Mediators Inflamm. 2008:129873, 2008) it was decided to determine whether GzmB could mediate VEGF release from endogenous matrix. VEGF was added to HUVEC-derived matrix and unbound VEGF was removed by washing.
  • VEGF release supernatants that were generated due to GzmB activity caused a significant increase in VEGFR2 phosphorylation in both Y1214 and Y1175 ( Figures 4A and 4B).
  • VEGF released from FN treated with GzmB + inhibitor lead to attenuated VEGFR2 activation.
  • VEGF that is released from FN by GzmB is active and can effectively lead to VEGFR2 phosphorylation in HUVEC.
  • mGzmB was co-injected with anti-mouse neutralizing VEGF antibody.
  • GzmB leads to VEGF dependent increase in vascular leakage in vivo.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes permettant de modifier les niveaux microenvironnementaux du facteur de croissance de l'endothélium vasculaire chez un sujet. Les méthodes consistent à fournir un inhibiteur de Granzyme B(GzmB) sur une zone d'inflammation. La zone d'inflammation peut être associée à des états ayant une augmentation associée de la perméabilité vasculaire, notamment l'arthrite rhumatoïde, l'infarctus du myocarde, les maladies oculaires, les maladies de la peau, telles que le psoriasis et la dermatite, les cancers, la transplantation, et/ou l'arthrosclérose, et des états similaires. L'inhibiteur de Granzyme B peut notamment être constitué d'un acide nucléique, d'un polypeptide, d'un anticorps spécifique Granzyme B, d'un dérivé d'anticorps Granzyme B, ou d'une petite molécule.
PCT/CA2014/050261 2013-03-15 2014-03-14 Méthodes et compositions pour l'inhibition de l'activité du facteur de croissance de l'endothélium vasculaire et de la perméabilité vasculaire Ceased WO2014139014A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361799608P 2013-03-15 2013-03-15
US61/799,608 2013-03-15

Publications (1)

Publication Number Publication Date
WO2014139014A1 true WO2014139014A1 (fr) 2014-09-18

Family

ID=51535733

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2014/050261 Ceased WO2014139014A1 (fr) 2013-03-15 2014-03-14 Méthodes et compositions pour l'inhibition de l'activité du facteur de croissance de l'endothélium vasculaire et de la perméabilité vasculaire

Country Status (1)

Country Link
WO (1) WO2014139014A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019183373A1 (fr) * 2018-03-21 2019-09-26 Northwestern University Petites molécules permettant de perturber le complexe de super-allongement et d'inhiber l'allongement de la transcription pour une cancérothérapie
CN112261939A (zh) * 2018-02-13 2021-01-22 塞托赛特生物制药股份有限公司 粒酶b定向成像和疗法
EP3700524A4 (fr) * 2017-10-26 2021-08-25 Emory University Inhibiteurs de mcl-1, compositions et utilisations dans la prise en charge du cancer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003065987A2 (fr) * 2002-02-04 2003-08-14 Merck & Co., Inc. Inhibiteurs de granzyme b

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003065987A2 (fr) * 2002-02-04 2003-08-14 Merck & Co., Inc. Inhibiteurs de granzyme b

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOIVIN ET AL.: "Intracellular versus granzyme B in immunity and disease: challenging the dogma", LABORATORY INVESTIGATION, vol. 89, November 2009 (2009-11-01), pages 1195 - 1220, XP055111045, DOI: doi:10.1038/labinvest.2009.91 *
HENDEL ET AL.: "Granzyme B Releases Vascular Endothelial Growth Factor from Extracellular Matrix Stores and Induces Vascular Permeability in vivo", ATHEROSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, vol. 33, no. 5 SUPP, May 2013 (2013-05-01), pages A326 *
PARDO ET AL.: "Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of pertorin", CELL DEATH AND DIFFERENTIATION, vol. 14, June 2007 (2007-06-01), pages 1768 - 1779 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3700524A4 (fr) * 2017-10-26 2021-08-25 Emory University Inhibiteurs de mcl-1, compositions et utilisations dans la prise en charge du cancer
US11524000B2 (en) 2017-10-26 2022-12-13 Emory University Targeting Mcl-1 to enhance DNA replication stress sensitivity for cancer therapy
CN112261939A (zh) * 2018-02-13 2021-01-22 塞托赛特生物制药股份有限公司 粒酶b定向成像和疗法
JP2021512964A (ja) * 2018-02-13 2021-05-20 サイトサイト バイオファーマ インコーポレイテッド グランザイムｂ指向性画像化および治療
EP3752145A4 (fr) * 2018-02-13 2021-11-17 Cytosite Biopharma Inc. Imagerie du granzyme b et thérapie dirigées contre le granzyme b
US11667645B2 (en) 2018-02-13 2023-06-06 Cytosite Biopharma Inc. Granzyme B directed imaging and therapy
WO2019183373A1 (fr) * 2018-03-21 2019-09-26 Northwestern University Petites molécules permettant de perturber le complexe de super-allongement et d'inhiber l'allongement de la transcription pour une cancérothérapie
US11453640B2 (en) 2018-03-21 2022-09-27 Northwestern University Small molecules for disrupting the super elongation complex and inhibiting transcription elongation for cancer therapy

Similar Documents

Publication Publication Date Title
JP6134268B2 (ja) 創傷治癒を促進するためのグランザイムｂ阻害剤組成物、方法および使用
US20080269123A1 (en) Methods for treating polycystic kidney disease (PKD) or other cyst forming diseases
US20240082211A1 (en) Soluble epoxide hydrolase as a target for ocular diseases
JP2010500363A (ja) 感染症とその後遺症を治療、または制御、または軽減、または改善するための組成物と方法
WO2013159082A1 (fr) Composés et méthodes pour la régulation d'intégrines
AU2017281980B2 (en) Wnt inhibitors for use in the treatment of fibrosis
AU2010243314B2 (en) Phosphotetrahydropyran compounds for the treatment of wounds and fibrotic disorders
US9717727B2 (en) Methods of treating and preventing leukemia and other cancers of the blood and bone
WO2014139014A1 (fr) Méthodes et compositions pour l'inhibition de l'activité du facteur de croissance de l'endothélium vasculaire et de la perméabilité vasculaire
KR101298826B1 (ko) 해리된 글루코코르티코이드 수용체 효능제를 포함하는, 전안부 염증을 치료하거나 또는 제어하기 위한 조성물
KR20140035481A (ko) 염증성 통증을 치료하거나, 제어하거나, 감소시키거나 또는 개선하기 위한 조성물 및 방법
KR20230041680A (ko) 안구 질환 치료제로서의 trpv4 억제제
ES2425178T3 (es) Composiciones y métodos para el tratamiento o la prevención del glaucoma o de su progresión
EP2717869B1 (fr) Méthodes de traitement à l'aide d'un inhibiteur de bcat1
KR20180002676A (ko) Cathepsin c 및/또는 cela1 및/또는 cela3a 및/또는 그와 관련된 구조적 효소를 타겟으로 하여 세포 또는 조직의 감염을 치료 및/또는 예방하기위한 조성물
CA2857546A1 (fr) Procedes de traitement et de prevention de maladies oculaires
Kanmani et al. Enhancement of autophagy in macrophages via the p120-catenin-mediated mTOR signaling pathway
Görög The Role of Ca2+ Signaling in the Physiology and Pathophysiology of the Pancreatic Ductal Cells
EP3589304A1 (fr) Compositions d'un inhibiteur du granzyme b et méthodes de prévention et/ou de traitement de la formation de cloques et/ou du pelage de la peau
JP2022506341A (ja) 処置、予防、および診断の方法
Malla Role of autophagy in caerulein induced pancreatitis

Legal Events

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

Ref document number: 14763834

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14763834

Country of ref document: EP

Kind code of ref document: A1