WO2018112128A1 - Analogues d'arbidol ayant une puissance améliorée vis-à-vis de l'hémagglutinine d'influenza - Google Patents

Analogues d'arbidol ayant une puissance améliorée vis-à-vis de l'hémagglutinine d'influenza Download PDF

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WO2018112128A1
WO2018112128A1 PCT/US2017/066275 US2017066275W WO2018112128A1 WO 2018112128 A1 WO2018112128 A1 WO 2018112128A1 US 2017066275 W US2017066275 W US 2017066275W WO 2018112128 A1 WO2018112128 A1 WO 2018112128A1
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mhz
compound
arbidoi
mmoi
binding
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PCT/US2017/066275
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Ian A. Wilson
Dennis W. WOLAN
Zoë V .F. WRIGHT
Rameshwar U. KADAM
Nicholas C. WU
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The Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/18—Testing for antimicrobial activity of a material
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • 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
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • 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
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/11—Orthomyxoviridae, e.g. influenza virus

Definitions

  • the 2008 pandemic demonstrated the speed with which the infection can spread across the globe and highlighted the eonsiderable limitations on current protection strategies. Whilst vaccines have produced. Some control over the risk of Infection, rapid antigenic drift makes the selection of strains an annual challenge.
  • Arbidoi (Umifenovir) is a broad-spectrum antiviral against a number of viruses, including influenza, Ebola and hepatitis B & C, Despite the lack of a m . echani . sm-of-action against any target virus, Arbidoi is clinically used- in Russia and China and is. currently in phase IV US clinical trials ⁇ clinicaitriais.gov/ct27show/NC-T01651663 ⁇ .
  • One major drawback to the use of Arbidoi is. the large dose required to achieve therapeutic efficiency.
  • Several groups have tried to improve the therapeutic potential by changing the substituents decorating the indole core ( Figure 1).
  • the invention provides, in various embodiments, a method of inhibiting the bioactivily of a virai hemagglutinin (HA) molecule that is displayed on the susface of the influenza virus, comprising contacting the hemagglutinin molecule -with an effective concentration of a virai hemagglutinin (HA) molecule that is displayed on the susface of the influenza virus, comprising contacting the hemagglutinin molecule -with an effective concentration of a virai hemagglutinin (HA) molecule that is displayed on the susface of the influenza virus, comprising contacting the hemagglutinin molecule -with an effective concentration of a virai hemagglutinin (HA) molecule that is displayed on the susface of the influenza virus, comprising contacting the hemagglutinin molecule -with an effective concentration of a virai hemagglutinin (HA) molecule that is displayed on the susface of the influenza virus, comprising contacting the hemagglut
  • the compound of formula (A) can be the compound of formula 11
  • the invention provides a method of treating or preventing an influenza viral infection in a patient, comprising administering to the patient an rmula (A)
  • the compound of formula (A) can be the compound of formula 11
  • FIG. 2 Synthesis of Arbidoi and Analogues. Reagents and Conditions: ⁇ ! acetic anhydride, pyridine (il) Mel, NaH, D F (iii) 8r 2 , CC (iv) thiophehbi, OH, MeOH (v) ' ⁇ , ⁇ , ⁇ ',- ⁇ '- tetramethyidiaminomethane, 1 ,4-dioxane (yi) mine, 1 ,4-dioxane (vfi) R"SH, KOH, MeOH Figure 3: Analogues of Arbidoi
  • Figure 5 Additional Analogues of Arbidoi based on 11. Compound 20 could not be synihesised using the synthetic route described as amine addition to the phenol was observed as well as amine addition to the indole.
  • Crystaiiographic data highlighted the importance of a water molecule in the binding pocket in the .meta position with respect to the thiophenoi group.
  • these analogues were synthesized with and without the presence of the amine- in position 4 on the indole, as well as replacing the amine with a piperazine to see if any further interactions towards the back of the binding pocket could be beneficial.
  • Ka was determined by bioiayerinterferomeiry (BLI) using an Octet Red instrument (ForteBio),
  • Biotinylated HAs purified as- described previously, were, used for these measurements-.
  • HAs at -10-50 ⁇ -sg ml "1 in 1 ⁇ kinetics buffer (1 ⁇ PBS, pH 7.4, 0.01% BSA and 0.002% Tween 20) were loaded onto streptavidin-eoated biosensors and incubated with varying concentrations of small molecule in solution.
  • the ratio- of fcn to k determines the % reported here.
  • Arbidoi I is a broad-spectrum antiviral which can be used, to treat influenza infection from both group 1 and group 2 viruses.
  • each compound was assessed for binding against one HA from group 1 (PR8; A/Puerto Rico/8/1934) and one from group 2 (HK68: A/Hong Kong/1 /68).
  • the mechanism-of-action of Arbidol is to prevent the low pH induced conformational change in HA through stabilization of the pre-fusipn conformation of HA. .
  • Trypsin susceptibilit (IS) assay ' was perf ormed on compound 11 to see if binding to HA woufd have a similar effect to Arbidol.
  • HA is readily converted into a protease-susceptible post-fusion form ⁇ Figure 6, Lanes 1 and 2)
  • Arbidol has been shown to prevent conversion of P ' ' 8 HA at pH 5 and thereby prevent ' trypsin digestion.
  • Compound 11 was found to show the -same effect (Figure 6, Lane 4), which ' was consistent with the result observed for the fusion-inhibiting stem targeting antibody GR911 Fab ( Figure 6, Lane 3).
  • the Trypsin susceptibility assay confirmed that compound 11 acted in the same way as ArbidoL namely by -stabilizing the pre-fusion complex and thus preventing fusion from occurring.
  • TS Trypsin susceptibility assay
  • the only treatments for influenza involv either inhibiting the M2 Ion channel inhibitors or neuraminidase. These mechanisms have been shown to be prone to antigenic drift and indeed resistance to these drugs has already been reported in th clinic.
  • Arbidoi has been shown to have both a novel mechanism of action and a novel binding site but needs to be admiriistered in fairly high doses to achieve therapeutic concentrations in blood plasma.
  • compound 11 shows a much higher binding affinity in the BLi assay, it is possible that the dosage required to reach peak therapeutic efficiency would be far less with respect to the parent compound.
  • Sodium bicarbonate refers to a saturated solution of sodium hydrogen carbonate in water. All water used was either distilled using a Miliipore Mil HQ® water purifier with Q-Gard® 2 column and 0,22 ⁇ filter from mif!ipore or used directly from a bottle of HPLC-grade water. Ail reactions were carried out in closed systems under Argon.
  • NM.R spectra were recorded using a Bruker AVili HD-600, DRX-500, AVI 11-400 and DPX-40G spectrometer (600 MHz, 500 MHz, 400 ' MHz and 400 MHz, respectively) and ail samples were dissolved in deuiera ted chloroform unless otherwise stated.
  • Offline data processing was carried put using the Mest ' reN.ova software " . Chemical shifts (5) are given in; ppm units- relative to tetramethylsilane and coupling constants (J) are measured in Hertz.
  • Proton (1 H) NMR multiplicities are shown as s (singlet), d (doublet), t (triplet), q (quartet), m (mu!tiplet) ' , dd (double doublet), dt ⁇ double triplet), dq (doublet of quartets), dt (doublet of triplets), ti (triplet of triplets), br s (broad singlet), br d (broad doublet).
  • MS refers to low resolution mass spectrometry and H RMS. refers to high resolution mass spectrometry.
  • Eiectrospray ionization (ESI) accurate mass was determined using a ThermoFinnigan LTQ Ion Trap, Flash column chromatography was carried out using silica gel with particle, size ⁇ 60 rn- and reverse phase column .chromatography was carried out using silica gel 60 silanized (53-200 ⁇ ). Thin layer chromatography (TLC) was performed on aluminium backed ' Sigma-Aldrich TLC plates with. FIM fluorescent indicator: Developed plates were air dried and analysed under a. UV light or by staining with the appropriate indicator.
  • NM ⁇ » (40Q MHz, CDCls) 8.34 (1 H, s; H), 7.75 (1H, s, «» ⁇ , 7.21 (1 H , d, J 8.5, He), 6.89 (1 H, d, J 8.5, 7 ⁇ 4.38 (2H, q, J 7.1 , C0 2 CH 2 CH 3 ), 2.71 (3H, e, CiCH 3 ), 2.34 (3H, s, Cq a CH 3 ), 1.43 (3H, t, J 7.1 , CO 2 0H 2 C « 3 ).
  • ArbidoS [EthyH 6 ⁇ bromo-4 ⁇ (dimeihyiamino)metliyl) ⁇ S ⁇ hydr xy ⁇ 1 ⁇ m3 ⁇ 4thyl-2- ⁇ pheny!thio)methyl -1 f/-indole-3-carboxylate] 4: ; Indole 3 (200 mg, 0,476 mmof, 1.0 eq.) and N, N, N' f W ? etramethyldi.amtnometha.ne (1-95 pL, 1.43 mmol, 3,0 eq.) were dissolved in 1 ,4- dsoxane (2 mi.). The reaction was.
  • carboxy ate 8a 3-hydrpxy htophenol. (117 pL, 1 , 15 mmol, 1.0 eq.) was added to a solution of sodium carbonate (367 mg, 3.46 mmoi, 3.0: eq.) and bromo indole 2 (500 mg, 1.15 mmol, 1.0 eq.) in dry ethyl acetate (10 mL). The reaction was heated to TOO °C and stirred for 5 h before cooling, filtering and removing the solvent in vacuo. The compound was purified by column chromatography (40% EtOAc in Hexanes) to produce the title product as a pale yellow solid (240 mg, 44%). HMR: ⁇ « (500 MHz,.
  • carboxyiate 8 Sodium carbonate (106 mg. 1.00 mmoi-, 2.0 eq.) was -added to a stirred solution of meta-hydfoxy indole 8a (240 mg, 0.502 mmoi, 1.0 eq.) in methanol (40 ml) and left to stir for 2h, The solution was then filtered and the solvent removed in vacuo, The product was re- dissolved in ethyl acetate (10 ml..) and washed once with water (40
  • methyM ff-irs o!e-S-carfeoxyiate 12 eia-amino Indole 14 104 mg, 0.238. mmot, 1.0 eq.) and V, ⁇ /, ⁇ , A/' eti3 ⁇ 4rnethyidfami omethane (1.95 ⁇ , 1 ,43 mmoi, 3.0 eq.) were dissolved in 1 ,4- dioxane (1.5 ml). The reaction was heaied to reflux for 3.5 h before removing the solvent in vacuo. The product was purified using preparative TIC to yield a paie yellow solid ⁇ 13 mg, 11 %).
  • Maphthatenyl indole 10 (1 12 mg, 0.238 mmoi, 1.0 eq.) and ⁇ /V ⁇ A/'-tetramethyidraminornethane (195 ⁇ _, 1 .43. mmoi, 3.0 eq.) were dissolved in 1 ,4-dioxane ( 1.5 mL). The reaction was heated, to reflux for 3.5 h .before removing the solvent in vacuo. The product was purified using preparative TIC to yield a pale yellow solid (26 mg, 20%).
  • car boxy ate 18 2-hydroxythiophenol (26.0 ⁇ , 0.256 mmoi, 1.0 eq.) was added to a solution of sodium carbonate (81 ,0 mg, 0.767 mmoi, 3.0 eq.) and promo indole 2 (1 00 mg, 0.256 mmoi, 1 .0 eq.) in ethyl acetate ⁇ 2 mL). The reaction was heated to 50 °C and stirred for 2 h before cooling and removing the solvent in vacuo. The product was then re-dissolved in methanol (2 ml.) and potassium hydroxide (21 ,5 mg, 0.384 mmoi, 1.5 eq , ⁇ was added.
  • carboxylase 17 4 iydroxythiophenol (26.0 pL, 0.256 mmoi, 1 .0 eq.) was added to a solution of .sodium carbonate (81.0 mg, 0,767 mmoi, 3.0 eq.) and bromo indole 2 (100 mg, 0.256 mmoi, 1.0 eq.) in ethyl acetate (2 mL). The reaction was heated to 50 °C. and stirred for 2 h before cooling and removing the solvent . in vacuo. The product was then re-dissolved in methanol ⁇ 2 mL) and potassium hydroxide (21 ,5 mg, 0,384 mmo!, 1,5 eq.) was added.
  • carboxyf ate 18a 3 ⁇ methpxythiophenoi (14.6 ⁇ ' !_, 0.118 mmo!, 1.0 eg.) was added to a solution of sodium carbonate (37.4 mg, 0.353 rrtmoi, 3.Q eq.) and bromo indoles 2 (46.0 mg, 0.118 rornoi, .0 eq.) in dry ethyl acetate (20 ml). The reaction was heated to 50 °C and stirred for 2 h before addition of water. The organic layer was separated, dried (Na ⁇ O ) and concentrated .in vacuo.
  • carboxyla e 18 Sodium carbonate (41.3 mg, 0.390 mmol, 2.0 eq.) was added to a stirred solution of meta-methoxy indole 18a (96,0 mg, 0.195 mmot, 1.0 eq.) in methanol (10 mL) and left to stir for 2h, The solution was then filtered and the solvent removed in vacuo.
  • HMR 3 ⁇ 4 H (500 MHz, MeOD) 7.53 (s, 1 ⁇ , H 7 ), 7.19 - 7,11 (m, 1H, 7.6, .7 Hz, 1H, # «), 6 -86 - 6.78 (m, TH, H ), 6.63 (dt, J - 13.7, 7.6 Hz, 1H, H f5 ), 4.48 (s, 2H, C1 ⁇ 2Sph), 4.34 (s, 2H, CM>NMe 2 ), 4.22 (dq, J * 10.8, 7,1, 6.3 Hz, 2H, C0 2 GH 2 CHs), 3.56 (s, 3H, HCH 3 ), 2.49 (d, J* 11.4 Hz, 6H, CH 2 N(CW 3 ) 2 ), 1.42 ⁇ 1.37 (m, 3H, COzCH ⁇ CHs.
  • methyi-1 f -indoie-S-car oxyiaie 21 Sodium carbonate (17,5 mg, 0165 mmoi, 3.0 eq.) was added to a stirred solution of meta-rnethoxy indole 18 (27.0 mg, 0.055 mmoi, 1.0 eq.) in- ethyl acetate (8 mi.. ⁇ and methanol (1 mL). The solution was left to stir for 3h before filtering and removing the solvent in vacuo.
  • OCTET Bio-Layer fnierferomelry Data and Testing ⁇ was determined by BLJ using an Octet Red instrument (ForteBio). Biofinylated HAs, purified as described previously", were used for these measurements. HAs at -10-60 pg m! "1 m i x kinetics buffer (1 * PBS, pH 7.4, 0.01 % BSA and 0.002% Tween 20). ere loaded onto streptavid in- coated biosensors and incubated with varying concentrations of small molecule in solution.. All binding data were collected -at 30. °C.
  • the experiments comprised five steps: (1 ) baseline acquisition ⁇ 60 s); (2) HA loading onto sensor (1800 s); (3) second baseline acquisition (120 s); (4). association of small molecule for the measurement of fen (180 s); and (5) dissociation of small molecule for the. measurement of feff (18Q s). Baseline and dissociation steps were carried out in. buffer only. The ratio of f w - to fe « determines the % reported here.

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Abstract

L'invention concerne une série d'analogues d'arbidol ayant une activité de liaison améliorée à l'hémagglutinine d'influenza. Par conséquent, l'invention peut offrir un procédé d'inhibition de la bioactivité de l'activité de l'hémagglutinine virale, ce qui est une étape essentielle dans l'entrée de particules virales infectieuses dans des cellules hôtes. L'invention peut également fournir une méthode de traitement de l'influenza, comprenant l'administration d'une quantité efficace d'un composé de formule (A), dans laquelle X représente S ou O, à un patient atteint d'influenza.
PCT/US2017/066275 2016-12-16 2017-12-14 Analogues d'arbidol ayant une puissance améliorée vis-à-vis de l'hémagglutinine d'influenza WO2018112128A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116003308A (zh) * 2022-12-27 2023-04-25 石家庄中硕制药有限公司 阿比多尔结晶方法

Citations (3)

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Publication number Priority date Publication date Assignee Title
US20090326037A1 (en) * 2005-12-28 2009-12-31 Irina Anatolievna Leneva Medicinal Agent For Treating Viral Infections
US7960427B2 (en) * 2004-03-12 2011-06-14 Shenyang Pharmaceutical University 5-hydroxyindole-3-carboxylate derivatives and uses thereof
WO2014075618A1 (fr) * 2012-11-15 2014-05-22 沈阳药科大学 Dérivé de 5-hydroxyindole contenant un noyau hétérocyclique et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7960427B2 (en) * 2004-03-12 2011-06-14 Shenyang Pharmaceutical University 5-hydroxyindole-3-carboxylate derivatives and uses thereof
US20090326037A1 (en) * 2005-12-28 2009-12-31 Irina Anatolievna Leneva Medicinal Agent For Treating Viral Infections
WO2014075618A1 (fr) * 2012-11-15 2014-05-22 沈阳药科大学 Dérivé de 5-hydroxyindole contenant un noyau hétérocyclique et son utilisation

Non-Patent Citations (2)

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WRIGHT ET AL.: "Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 27, 15 August 2017 (2017-08-15), pages 3744 - 3748, XP085144487 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116003308A (zh) * 2022-12-27 2023-04-25 石家庄中硕制药有限公司 阿比多尔结晶方法
CN116003308B (zh) * 2022-12-27 2023-09-29 石家庄中硕制药有限公司 阿比多尔结晶方法

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