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WO2019126860A1 - Composition pharmaceutique pour le traitement d'une infection causée par un virus de la famille flaviviridae, et utilisation de cette composition - Google Patents

Composition pharmaceutique pour le traitement d'une infection causée par un virus de la famille flaviviridae, et utilisation de cette composition Download PDF

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Publication number
WO2019126860A1
WO2019126860A1 PCT/BR2018/050489 BR2018050489W WO2019126860A1 WO 2019126860 A1 WO2019126860 A1 WO 2019126860A1 BR 2018050489 W BR2018050489 W BR 2018050489W WO 2019126860 A1 WO2019126860 A1 WO 2019126860A1
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WIPO (PCT)
Prior art keywords
virus
viruses
flaviviridae family
infection caused
compound
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Ceased
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PCT/BR2018/050489
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English (en)
Portuguese (pt)
Inventor
Lucio Holanda Gondim de FREITAS JUNIOR
Carolina Borsoi Moraes Holanda DE FREITAS
Denise Regina Bairros DE PILGER
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INSTITUTO BUTANTAN
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INSTITUTO BUTANTAN
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Priority claimed from BR102017028623-1A external-priority patent/BR102017028623B1/pt
Application filed by INSTITUTO BUTANTAN filed Critical INSTITUTO BUTANTAN
Publication of WO2019126860A1 publication Critical patent/WO2019126860A1/fr
Anticipated expiration legal-status Critical
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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • 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
    • A61K31/41—Heterocyclic 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
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention is in the field of biochemistry and pharmacology.
  • the present invention relates to a pharmaceutical composition for the treatment of infection caused by Flaviviridae family viruses and to the use of said pharmaceutical composition for the manufacture of a medicament for the treatment of infection caused by Flaviviridae family viruses.
  • the Flaviviridae family is composed of the genera Flavivirus, Pestivirus and Hepacivirus.
  • the genus Flavivirus comprises more than 70 viruses circulating on virtually all continents except Antarctica.
  • Mosquito-borne flaviviruses such as yellow fever virus, serotypes of dengue virus 1-4, Japanese encephalitis virus and West Nile virus cause endemic and epidemic diseases with a high mortality rate around the world.
  • Flaviviruses are encoded by a single-stranded, single-stranded sense genome RNA of approximately 11 kb in length.
  • the genome is a single open reading frame coding for 10 viral proteins that are cleaved co- and post-translationally from the polyprotein, the capsid (C), membrane (M) and envelope (E) structural proteins and non-structural proteins (NS) 1, 2A, 2B, 3A, 4B and 5.
  • the polyprotein is flanked by 5 'and 3' non-coding regions (Lindenbach & Rice, 2003) Syndromes that cause human infection with flaviviruses range from asymptomatic infections to serious and sometimes fatal diseases, including haemorrhagic manifestations of severe yellow fever and dengue virus infection and encephalitis caused by infection with Japanese encephalitis virus and virus (Barrett & Higgs, 2007; Barrett & Monath, 2003; Gubler, 2004).
  • Yellow fever is endemic in several regions of South America and Africa and is spread by the Aedes aegypti, the mosquito that also carries the dengue virus and Zika.
  • Early symptoms - fever, nausea, vomiting and muscle pain - are fairly mild and usually last only 3 to 4 days. About 15% of those affected by the disease, however, present a second most toxic phase 24h after recovery from the initial symptoms. Patients experience severe abdominal pain, become jaundiced, and bleeding from the mouth, nose, eyes, or stomach may occur. About half of people who enter the toxic phase die within 7 to 10 days.
  • the present invention relates to the screening of a library of pharmacologically active compounds containing various experimental and clinically useful drugs for the detection of inhibitors of yellow fever virus infection.
  • the work utilized the High Content Screening (HCS) or High Content Screening strategy. This technology allows collections of chemical compounds, both of synthetic and natural origin, to be rapidly triadic against the virus in a physiological environment, with the virus infecting human cells.
  • HCS High Content Screening
  • This technology allows collections of chemical compounds, both of synthetic and natural origin, to be rapidly triadic against the virus in a physiological environment, with the virus infecting human cells.
  • composition of the present invention comprising the compound of formula (I) defined herein and a pharmaceutically acceptable carrier for the treatment of infection caused by Flaviviridae family viruses and nor their use for the production of a medicament for the treatment of infection caused by viruses of the Flaviviridae family.
  • Vaccination is an important way of preventing yellow fever.
  • risk groups that can not benefit from such prevention, such as people over 60, babies under 9 months, pregnant women or people with immunodeficiency.
  • there has already been an epidemic of the disease in Angola and, apparently, there are risks of the disease spread throughout Asia, specifically high population rate such as China and India.
  • There are many Chinese workers in Angola and there is probably not enough vaccine for everyone if the virus reaches these high-index countries. In this sense, it is important to treat the disease so that there is an increase in the rate of survivors.
  • At the moment there is no specific antiviral treatment for yellow fever only care to treat dehydration, liver and kidney failure and fever. This fact demonstrates the importance of this patent application.
  • the present invention relates to a pharmaceutical composition for the treatment of infection caused by Flaviviridae family viruses comprising the compound defined by formula (I)
  • the compound defined by formula (I) can be used in the concentration of 12.5 mM to 25 mM. In a further embodiment, the compound defined by formula (I) is preferably used at the concentration of 12.5 mM.
  • the invention relates to the use of the composition as defined above for the manufacture of a medicament for the treatment of infection caused by viruses of the Flaviviridae family.
  • viruses of the Flaviviridae family include viruses selected from the group consisting of: West Nile virus, dengue virus, Zika virus, encephalitis virus transmitted by tick, St. Louis encephalitis virus, hepatitis C and yellow fever virus.
  • the virus infection caused by the Flaviviridae family is caused by the yellow fever virus.
  • FIG. 1 High Content Analysis representative images of Huh7 (blue) cells infected with YFV-YFP (yellow) stained with DAPI 72 h after infection.
  • the images show the process of automated image analysis: A) raw data; B) segmentation of host cell nuclei; C) segmentation of host cell cytoplasm; D) YFP intensity; E) Infected cells (green).
  • FIG. 2 Screening of LOPAC1280 library against YFV-YFP. Correlation between cellular rate (Y axis) and normalized activity (X axis). Negative control represented by red dots [(-) DMSO]; blue spots indicate wells treated with 6.25 ng / mL of Interferon alfa 2A [positive control - (+) EC100]; green dots indicate wells infected with mock [positive control - (+) MOCK]; the orange dot represents the sample selected for secondary screening [hit] - normalized activity of more than 70% and cell rate close to 0.8.
  • Negative control represented by red dots [(-) DMSO]; blue spots indicate wells treated with 6.25 ng / mL of Interferon alfa 2A [positive control - (+) EC100]; green dots indicate wells infected with mock [positive control - (+) MOCK]; the orange dot represents the sample selected for secondary screening [hit] - normalized activity of more than 70% and cell rate close to
  • Figure 3 Representative images obtained from the Operetta High Content System (objective of 20x WD - DNA staining with DAPI) showing the controls, the reference compound Interferon alpha 2A (at 6.25 ng / mL) - ECiocv control negative (DMSO) and positive (mock-infected) control, in addition to various concentrations of compound HA155-LOPAC-886.
  • Figure 4 Antiviral activity of compound HA155-LOPAC-886 YFV-YFP infecting host cell Huh7.
  • Left-Y axis normalized activity values (black points and curves);
  • Right-Y axis normalized cell rate values (squares and red curves);
  • X axis Compound log / sample concentration. The mean values (points and squares) and the standard deviation (bars) are shown. Data from two independent experiments.
  • the present invention relates to a pharmaceutical composition for the treatment of infection caused by Flaviviridae family viruses comprising the compound as defined by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the compound defined by formula (I) may be used in the concentration of 12.5 to 25 mM.
  • the compound defined by formula (I) is preferably used at the concentration of 12.5 mM.
  • the compound of formula (I) is an inhibitor of autotaxin IV.
  • Autotaxin converts lysophosphatidylcholine to lysophosphatidylic acid (LPA), which can mediate changes in cell proliferation, angiogenesis and cytokine secretion.
  • LPA lysophosphatidylic acid
  • Dose-dependent blockade of thrombin-induced LPA secretion in platelets has been demonstrated (Fulkerson Z et al, 2011).
  • ATX Autotaxin
  • LPC lysophosphatidylcholine
  • LPA lysophosphatidic acid
  • HA155-LOPAC-886 Molecular coupling indicated a remarkable binding form for one of the isomers, which differed from the original binding form of HA155-LOPAC-886 to ATX.
  • the thrombin-mediated increase in platelet-derived LPA was completely attenuated in a dose dependent manner by HA155-LOPAC-886.
  • HA155 - LOPAC-886 could inhibit autotaxin by selective binding to its catalytic threonine.
  • HA155-LOPAC-886 has been shown to dose-dependently block platelet-mediated thrombin-induced LPA secretion (Albers, H. M. H. et al., 2011 and Fulkerson Z et al, 2011).
  • the use of the term "pharmaceutically acceptable” essentially means being nontoxic to the subject to which the Pharmaceutically acceptable material is administered.
  • the use of the term "pharmaceutically acceptable carrier” means a nontoxic, inert solid, semisolid liquid excipient, diluent, auxiliary formulation of any type, such as saline, except water.
  • materials that may serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, cyclodextrin; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols, such as glycerinaglycol, sorbitol, mannitol and polyethylene; esters, such as ethyl laurate, ethyl oleate, agar; buffering agents, such as aluminum hydroxide and magnesium hydroxide; alg
  • Flaviviridae family virus is used in this application as a synonym for "flavivirus” and “flavivirose” as synonymous with “infection caused by Flaviviridae family viruses”.
  • composition for the production of a medicament for the treatment of infection caused by the family virus Flaviviridae
  • the present invention relates to the use of the composition as defined above for the manufacture of a medicament for the treatment of infection caused by Flaviviridae family viruses.
  • the virus infection of the Flaviviridae family includes viruses selected from the group consisting of: West Nile virus, dengue virus, Zika virus, tick-borne encephalitis virus, St. Louis encephalitis virus, hepatitis C virus and yellow fever viruses.
  • the virus infection caused by the Flaviviridae family is caused by the yellow fever virus.
  • the reference compound Interferon alpha 2A was obtained from Sigma-Aldrich.
  • the LOPAC1280 library containing 1280 samples was purchased from Sigma-Aldrich.
  • Huh7 The Huh7 cell line was derived from a human hepatic cell carcinoma. The cells form a contiguous monolayer that can be maintained for several weeks. This inventory was purchased from the Japanese Bioressources Research Collection (JCRB). This cell line was maintained in DMEM F12 medium (Sigma-Aldrich), supplemented with 10% FBS (Sigma Aldrich), 100 U / ml penicillin (GIBCO) and 100 ⁇ g / ml streptomycin (GIBCO), hereinafter described as " DMEM F12 ".
  • C6 / 36 The C6 / 36 cell line was derived from incubated larvae of Aedes albopictus. C6 / 36 cells exhibit adherent epithelial morphology. This inventory was provided by Prof. Dr. Amilcar Tanuri, from the Federal University of Rio de Janeiro. This cell line was maintained in L15 medium (Sigma-Aldrich), supplemented with 10% FBS
  • Yellow fever virus YDV-YD virus (YFV) 17D virus expressing the yellow fluorescent reporter protein (YFP) (YFV-YFP) was donated by Laura Gil (Aggeu Magalh ⁇ es Research Center, Fiocruz, Pernambuco , Brazil) . Yellow fever viruses were obtained from the supernatant of C6 / 36 tissue cultures infected with the virus. Infected cultures were maintained in L15 medium and frozen in 250 pL aliquots. Preparation of the compound solution
  • the sample library was sent into 96-well plates (25 ⁇ l / well) at a stock concentration of 10 mM in 100% dimethyl sulfoxide (DMSO). Samples were transferred manually to 384 well polypropylene stock plates (Mother plates) (Greiner Bio-One). These plates were used to prepare new plates in a lower concentration. Samples were transferred manually to new 384-well polypropylene plates (10 ⁇ l / well) at a final concentration of 1 mM in 100% DMSO. Prior to performing the assay, intermediate plates were prepared. Samples were diluted in the buffered saline solution (PBS IX) to a final concentration of 600 pM compound and 6% DMSO. The selected hits were collected from the 384-well motherboard.
  • PBS IX buffered saline solution
  • HCS allows the evaluation of samples having antiviral activity against infected Huh7 cells.
  • 10 ⁇ l of each sample were manually transferred from Greiner Bio-One plates to 384-well black polystyrene assay plates (Greiner Bio-One) by means of a multichannel pipette which yields a final concentration of 10 mM with 1.0% DMSO (100 fold dilution).
  • Infections were then performed with 3,000 Huh7 / well cells co-plated with MOI 2.5 of YFP-YFP, all resuspended in F12 DMEM and dispensed with the aid of a multichannel pipette.
  • the plates were incubated for 72 h at 37 ⁇ C / 5% CO 2 under a humidified atmosphere.
  • the plates were fixed with 4% paraformaldehyde (PFA), stained with DAPI (Sigma-Aldrich) for 30 minutes in the dark at room temperature and four images of each well were purchased from the High Content Imaging System Operetta (PerkinElmer) with 20X magnification.
  • the images were analyzed by Harmony's high content analysis software (HCA) (PerkinElmer) for identification, segmentation and quantification of the host cell nucleus, cytoplasm and intracellular parasites ( Figure 1).
  • HCA Harmony's high content analysis software
  • the HCA provided as output data for all images from one well the total number of cells, total number of infected cells and YFP intensity of infected cells.
  • IR Infection Rate
  • Activity Norrralizacfe (A) [1- (ft H3 ⁇ 4-A / P3 ⁇ 4) / (ft H3 ⁇ 4-A / P3 ⁇ 4 > )] x 100
  • Av. IR N mean infection rate of negative control wells.
  • Av. IRp mean infection rate of positive control wells.
  • Av. IR T mean infection rate of test compound wells (at a given concentration).
  • Av.IRp mean of infection rate of positive control
  • AV.IR N mean of infection rate of negative control
  • EC 50 was defined as the concentration of the compound corresponding to 50% normalized activity after 72 h incubation of the compound. Power refers to the EC50 - the more potent the compound, the lower its EC50 - while the efficacy is related to the maximum observed activity of a compound (in%) - the more effective the compound, the closer its maximum activity of 100%.
  • the same rationale is used for the CC50 definition: the compound concentration, which reduces the cell rate by 50%, when compared to the mean of negative control.
  • the LOPAC1280 library was screened at a 100-fold dilution, and the assay plates were considered approved with factor Z'30.5; the mean Z factor of the assay was 0.84 ⁇ 0.06.
  • the cell rate values of all samples tested in the library revealed that only 9.61% had host cell toxicity greater than 50% at the concentration tested ( Figure 2).
  • the primary hits were selected as the best twenty-eight more active samples yielding a host cell toxicity of 20% and normalized activity equal to or approximately 70% as the individual images of the wells tested were confirmed and confirmed the reduction of rate of infection. Selection of samples at primary screening resulted in a global hit rate of 2.18% ( Figure 2). The results stimulate the process with subsequent trials, since the concentration tested for hits on primary screening is considered low (10 mM).
  • selectivity index rate of CC 50 value by EC 50 value (CC 50 / EC 50 ). Whenever the CC 50 is not generated by curve fitting, the highest concentration tested is used to estimate the SI (Max [] tested / ECso). Whenever the EC 50 is not generated by curve fitting, the lowest concentration tested is used to estimate the SI (CC 50 / Min [] tested). The maximum activity was obtained from the value by the nonlinear regression curve.

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Abstract

La présente invention concerne une composition pharmaceutique pour le traitement d'une infection causée par un virus de la famille Flaviviridae, comprenant le composé tel que défini par la formule (I) ou un sel pharamceutiquement acceptable de celui-ci, et un véhicule pharmaceutiquement acceptable. La présente invention concerne également l'utilisation de la composition susmentionnée pour la production d'un médicament destiné au traitement d'une infection causée par un virus de la famille Flaviviridae.
PCT/BR2018/050489 2017-12-29 2018-12-28 Composition pharmaceutique pour le traitement d'une infection causée par un virus de la famille flaviviridae, et utilisation de cette composition Ceased WO2019126860A1 (fr)

Applications Claiming Priority (2)

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BRBR1020170286231 2017-12-29
BR102017028623-1A BR102017028623B1 (pt) 2017-12-29 Composição farmacêutica para o tratamento de infecção causada por vírus da família flaviviridae, e, uso da composição

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WO2019126860A1 true WO2019126860A1 (fr) 2019-07-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012024620A2 (fr) * 2010-08-20 2012-02-23 Amira Pharmaceuticals, Inc. Inhibiteurs de l'autotaxine et leurs utilisations
EP2203168B1 (fr) * 2007-09-18 2014-07-16 Stanford University Compositions pour le traitement d'une infection par un virus de la famille des flaviviridae

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2203168B1 (fr) * 2007-09-18 2014-07-16 Stanford University Compositions pour le traitement d'une infection par un virus de la famille des flaviviridae
WO2012024620A2 (fr) * 2010-08-20 2012-02-23 Amira Pharmaceuticals, Inc. Inhibiteurs de l'autotaxine et leurs utilisations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ALBERS, H.M.H.G. ET AL.: "Structure-Based Design of Novel Boronic Acid-Based Inhibitors of Autotaxin", J. MED. CHEM., vol. 54, 26 May 2011 (2011-05-26), pages 4619 - 4626, XP055078298, doi:10.1021/jm200310q *
NITSCHE, C. ET AL.: "Peptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology", J. MED. CHEM., vol. 60, no. 1, 2017, pages 511 - 516, XP055622746 *

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