[go: up one dir, main page]

WO2013178782A1 - Inhibiteurs allostériques de la protéase ns3 du virus de l'hépatite c virus - Google Patents

Inhibiteurs allostériques de la protéase ns3 du virus de l'hépatite c virus Download PDF

Info

Publication number
WO2013178782A1
WO2013178782A1 PCT/EP2013/061256 EP2013061256W WO2013178782A1 WO 2013178782 A1 WO2013178782 A1 WO 2013178782A1 EP 2013061256 W EP2013061256 W EP 2013061256W WO 2013178782 A1 WO2013178782 A1 WO 2013178782A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
protease
hepatitis
compounds
virus
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/EP2013/061256
Other languages
English (en)
Inventor
Adrian Velazquez-Campoy
Javier Sancho Sanz
Olga Abian Franco
Sonia VEGA SANCHEZ
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.)
Universiteit Gent
Instituto Aragones De Ciencias de la Salud
Universidad de Zaragoza
Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo ARAID
Original Assignee
Universiteit Gent
Instituto Aragones De Ciencias de la Salud
Universidad de Zaragoza
Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo ARAID
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 Universiteit Gent, Instituto Aragones De Ciencias de la Salud, Universidad de Zaragoza, Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo ARAID filed Critical Universiteit Gent
Publication of WO2013178782A1 publication Critical patent/WO2013178782A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/41641,3-Diazoles
    • A61K31/41841,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/192Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/41961,2,4-Triazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/472Non-condensed isoquinolines, e.g. papaverine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/473Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4738Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/576Immunoassay; Biospecific binding assay; Materials therefor for hepatitis
    • G01N33/5767Immunoassay; Biospecific binding assay; Materials therefor for hepatitis non-A, non-B hepatitis
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00Screening for compounds of potential therapeutic value
    • G01N2500/04Screening 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)

Definitions

  • the viral RNA is directly translated in infected cells into a precursor polyprotein which must be processed for successful viral
  • the present invention also provides a method for identifying compounds that can be used according to the present invention.
  • the present invention further provides a method for screening a compound capable of binding and stabilizing the Zn+2 -free NS3 protease conformation of the hepatitis C virus in a non-native inactive partially- folded conformation, wherein a compound library is subjected to a binding assay as illustrated herein in example 1 and 2 ,
  • esters of the compounds of this invention include C1-C6 alkyl esters, wherein the alkyl group is a straight or branched substituted or
  • prodrug refers to compounds that are rapidly
  • prodrugs are provided in . Higuchi and V . Stella, "Pro-drugs as Novel Delivery Systems , " Vol . 14 of the A. C . S .
  • the carrier or diluent ma- include ime delay material, such as glyceryl monoscearate or glyceryl distearate alone or with a wax, or other materials well known in the arc .
  • Huh 5-2 cells were seeded at a density of 5X 103 per well in a tissue culture-treated white 96 -well view plate [Techno Plastic Products AG, Switzerland) in complete DMEM supplemented with 250 /ig/iTiL G418. After incubation for 24 hours at 37°C (5% COG ⁇ medium was removed and 2-fold serial dilutions in complete DMEM (without G418) of the test compounds were added in a total volume of 100 ⁇ .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pathology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • General Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Physics & Mathematics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/EP2013/061256 2012-05-30 2013-05-31 Inhibiteurs allostériques de la protéase ns3 du virus de l'hépatite c virus Ceased WO2013178782A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12382218 2012-05-30
EP12382218.1 2012-05-30

Publications (1)

Publication Number Publication Date
WO2013178782A1 true WO2013178782A1 (fr) 2013-12-05

Family

ID=48577728

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/061256 Ceased WO2013178782A1 (fr) 2012-05-30 2013-05-31 Inhibiteurs allostériques de la protéase ns3 du virus de l'hépatite c virus

Country Status (1)

Country Link
WO (1) WO2013178782A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015035072A1 (fr) * 2013-09-04 2015-03-12 The Arizona Board Of Regents On Behalf Of The University Of Arizona Traitement et/ou prévention de métastases osseuses
KR101771784B1 (ko) 2015-02-17 2017-08-28 중앙대학교 산학협력단 Tlr2 신호전달계 관련 질병의 예방 및 치료용 약학 조성물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032177A2 (fr) * 1998-11-24 2000-06-08 Hollis-Eden Pharmaceuticals, Inc. Utilisation de composes 17-cetosteroides et de leurs derives, metabolites et precurseurs pour le traitement du virus de l'hepatite c ou autres togavirus
WO2006122156A2 (fr) * 2005-05-09 2006-11-16 Hydra Biosciences, Inc. Composes pour moduler la fonction trpv3
US20070213321A1 (en) * 2005-05-09 2007-09-13 Hydra Biosciences, Inc. Compounds for modulating TRPV3 function
WO2010020676A1 (fr) * 2008-08-20 2010-02-25 Vib Vzw Utilisation d’inhibiteurs de la topoisomérase de type i pour traiter des infections virales
WO2010101649A2 (fr) * 2009-03-05 2010-09-10 Pablo Gastaminza Inhibition du récepteur sigma 1 en tant que nouvelle approche thérapeutique contre une infection par le virus de l'hépatite c

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032177A2 (fr) * 1998-11-24 2000-06-08 Hollis-Eden Pharmaceuticals, Inc. Utilisation de composes 17-cetosteroides et de leurs derives, metabolites et precurseurs pour le traitement du virus de l'hepatite c ou autres togavirus
WO2006122156A2 (fr) * 2005-05-09 2006-11-16 Hydra Biosciences, Inc. Composes pour moduler la fonction trpv3
US20070213321A1 (en) * 2005-05-09 2007-09-13 Hydra Biosciences, Inc. Compounds for modulating TRPV3 function
WO2010020676A1 (fr) * 2008-08-20 2010-02-25 Vib Vzw Utilisation d’inhibiteurs de la topoisomérase de type i pour traiter des infections virales
WO2010101649A2 (fr) * 2009-03-05 2010-09-10 Pablo Gastaminza Inhibition du récepteur sigma 1 en tant que nouvelle approche thérapeutique contre une infection par le virus de l'hépatite c

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. URBANI: "The Metal Binding Site of the Hepatitis C Virus NS3 Protease. A SPECTROSCOPIC INVESTIGATION", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 273, no. 30, 24 July 1998 (1998-07-24), pages 18760 - 18769, XP055076030, ISSN: 0021-9258, DOI: 10.1074/jbc.273.30.18760 *
DE FRANCESCO ET AL: "Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER, vol. 59, no. 12, 10 October 2007 (2007-10-10), pages 1242 - 1262, XP022328021, ISSN: 0169-409X, DOI: 10.1016/J.ADDR.2007.04.016 *
F. ROOHVAND ET AL: "Initiation of Hepatitis C Virus Infection Requires the Dynamic Microtubule Network: ROLE OF THE VIRAL NUCLEOCAPSID PROTEIN", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 284, no. 20, 15 May 2009 (2009-05-15), pages 13778 - 13791, XP055076195, ISSN: 0021-9258, DOI: 10.1074/jbc.M807873200 *
OLGA ABIAN ET AL: "Conformational Stability of Hepatitis C Virus NS3 Protease", BIOPHYSICAL JOURNAL, vol. 99, no. 11, 1 December 2010 (2010-12-01), pages 3811 - 3820, XP055076078, ISSN: 0006-3495, DOI: 10.1016/j.bpj.2010.10.037 *
OLGA ABIAN ET AL: "Thermodynamics of zinc binding to hepatitis C virus NS3 protease: A folding by binding event", PROTEINS: STRUCTURE, FUNCTION, AND BIOINFORMATICS, vol. 77, no. 3, 15 November 2009 (2009-11-15), pages 624 - 636, XP055075941, ISSN: 0887-3585, DOI: 10.1002/prot.22475 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015035072A1 (fr) * 2013-09-04 2015-03-12 The Arizona Board Of Regents On Behalf Of The University Of Arizona Traitement et/ou prévention de métastases osseuses
US10179142B2 (en) 2013-09-04 2019-01-15 The Arizona Board Of Regents On Behalf Of The University Of Arizona Treatment and/or prevention of bone metastasis
KR101771784B1 (ko) 2015-02-17 2017-08-28 중앙대학교 산학협력단 Tlr2 신호전달계 관련 질병의 예방 및 치료용 약학 조성물

Similar Documents

Publication Publication Date Title
KR102794132B1 (ko) 니트릴-함유 항바이러스 화합물
CN114057702B (zh) 一种新型冠状病毒主蛋白酶的抑制剂及其制备方法和用途
WO2022021841A1 (fr) Inhibiteur principal de protéase du nouveau coronavirus, son procédé de préparation et son utilisation
Tsantrizos et al. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection
US9309284B2 (en) Macrocyclic and peptidomimetic compounds as broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, caliciviruses and coronaviruses
RU2401840C2 (ru) Ингибиторы iap
Sun et al. Structure-based design, synthesis, evaluation, and crystallographic studies of conformationally constrained Smac mimetics as inhibitors of the X-linked inhibitor of apoptosis protein (XIAP)
KR20120013450A (ko) 세린 프로테아제, 특히 hcv ns3-ns4a 프로테아제의 억제제
JP2008540537A (ja) チアゾール化合物および使用方法
Kühl et al. Beyond basicity: discovery of nonbasic DENV-2 protease inhibitors with potent activity in cell culture
KR20080033481A (ko) 세린 프로테아제의 억제제
JPWO2005063293A1 (ja) Sr蛋白質のリン酸化制御方法、および、sr蛋白質の活性制御剤を有効成分とする抗ウイルス剤
US9464064B2 (en) HCV helicase inhibitors and methods of use thereof
Ivanova et al. Optimization of substrate‐analogue furin inhibitors
KR20080066949A (ko) 바이러스 복제 억제제
WO2005043118A2 (fr) Methode de decouverte de medicament
S Straub Targeting IAPs as an approach to anti-cancer therapy
TW202304888A (zh) 醚連接之抗病毒化合物
CN107406485A (zh) 用于治疗癌症的肽
WO2013178782A1 (fr) Inhibiteurs allostériques de la protéase ns3 du virus de l'hépatite c virus
US20110064694A1 (en) Anti-hepatitis c activity of meso-tetrakis-porphyrin analogues
KR101861869B1 (ko) 신규한 비스-아미드 유도체 및 이의 용도
Rai et al. The changing face of hepatitis C: recent advances on HCV inhibitors targeting NS5A
RU2786722C1 (ru) Нитрилсодержащие противовирусные соединения
Wang et al. Current drug discovery for anti-hepatitis C virus targeting NS4B

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: 13727576

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 24/04/2015)

122 Ep: pct application non-entry in european phase

Ref document number: 13727576

Country of ref document: EP

Kind code of ref document: A1