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WO2024099346A1 - Utilisation d'un composé indazole dans le traitement de maladies médiées par l'activation de l'inflammasome - Google Patents

Utilisation d'un composé indazole dans le traitement de maladies médiées par l'activation de l'inflammasome Download PDF

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WO2024099346A1
WO2024099346A1 PCT/CN2023/130416 CN2023130416W WO2024099346A1 WO 2024099346 A1 WO2024099346 A1 WO 2024099346A1 CN 2023130416 W CN2023130416 W CN 2023130416W WO 2024099346 A1 WO2024099346 A1 WO 2024099346A1
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methyl
asc
carboxylic acid
alkyl
indazole
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Chinese (zh)
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银巍
陈晨
黄奕俊
颜光美
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Sun Yat Sen University
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    • 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
    • A61K31/415—1,2-Diazoles
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    • G16B35/20—Screening of libraries

Definitions

  • the present invention relates to the medical use of indazole compounds, and in particular to the use of lonidamine and its analogs in the treatment of diseases mediated by inflammasome activation based on the ASC-caspase-1 pathway.
  • LND Lonidamine
  • indazole-3-carboxylic acid that inhibits hexokinase, the rate-limiting enzyme in the glycolytic pathway.
  • LND was first reported as a candidate for contraceptives and then used as an anti-tumor drug due to its anti-Warburg effect of inhibiting glycolysis.
  • Recently, the anti-inflammatory effects of LND have been observed in animal models of ischemic stroke and arthritis, but its exact mechanism of action has not been fully elucidated.
  • Inflammasomes are multi-molecular protein complexes in cells that respond to innate immune recognition caused by microbial infection and endogenous danger signals and are one of the key steps in the inflammatory response. Inflammasomes are composed of pattern recognition receptors (PRRs), adaptor proteins, apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1.
  • PRRs pattern recognition receptors
  • ASC apoptosis-associated speck-like protein containing a CARD
  • caspase-1 caspase-1
  • PRRs include nucleotide-binding oligomerization domain (NOD) proteins, leucine-rich repeat (LRR) protein NLR (leucine-rich repeat (LRR)-containing protein) family members NLRP1 (NLR family, pyrin domain containing 1), NLRP3 (NLR family, pyrin domain containing 1) and NLRC4 (NLR Family CARD Domain Containing 4), as well as proteins absent in melanoma 2 (AIM2) and Pyrin.
  • NLRP3 can respond to a variety of stimuli, including bacteria, viruses, extracellular ATP, pollutants, metabolic disorders and tissue damage.
  • the senor binds to ASC and promotes ASC oligomerization to form ASC specks, which in turn recruits caspase-1 precursors and activates caspase-1.
  • Activated caspase-1 ultimately leads to the maturation and secretion of pro-inflammatory mediators IL-1 ⁇ and IL-18, and cleaves gasdermin D (GSDMD) to induce pyroptosis.
  • GDMD gasdermin D
  • ASC intracellular oligomerization to form ASC specks is necessary for the assembly and activation of a variety of inflammasomes.
  • extracellular ASC specks have been shown to have inflammatory signaling functions, including inducing neutrophil infiltration, accelerating A ⁇ deposition, and regulating adaptive immunity.
  • Increased ASC oligomers have been detected in the serum of patients with chronic respiratory diseases or autoinflammatory diseases, and ASC oligomers have also been detected in the cerebrospinal fluid of patients with subarachnoid hemorrhage and traumatic brain injury. Therefore, extracellular ASC specks can be used as potential biomarkers for these diseases.
  • inflammasome inhibitors In order to prevent and treat inflammasome-related diseases, inflammasome inhibitors with different targets have been designed and developed. Some compounds can directly bind to NLRP3 to block the activation of inflammasomes, including MCC950, CY-09, OLT1177, tranilast, and oridonin. Glyburide, BHB, and fenamate inhibit the activation of inflammasomes by inhibiting the upstream activation signals of NLRP3. However, since these upstream signals are involved in a variety of biological processes, these compounds can produce off-target effects and toxic side effects. For example, the highly selective and potent NLRP3 inhibitor MCC950 was terminated in a Phase II clinical trial for the treatment of rheumatoid arthritis due to liver toxicity. At present, these inflammasome inhibitors have shown therapeutic effects in experimental animal models, but have not been clinically used to treat various inflammatory-related diseases. In addition, inflammasome inhibitors with other non-NLRP3 targets are rarely reported.
  • ASC oligomerization is a key event in the assembly of inflammasomes, and the dysregulated activation of inflammasomes has been shown to be associated with the development and prognosis of a variety of diseases. Without being bound by theory, the inventors believe that blocking ASC oligomerization prevents inflammasome assembly events and ASC spot formation, thereby inhibiting the dysregulated activation of inflammasomes, and can be used to treat diseases mediated by inflammasome activation based on the ASC-caspase-1 pathway.
  • One aspect of the present invention provides the use of a compound of formula Ia or Ib in the preparation of a drug for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway.
  • R1 is selected from hydrogen, halogen, C1-3 alkyl, amino, C1-3 alkylamino and halogenated C1-3 alkyl
  • R2 is selected from carboxyl, C1-3 alkyl and hydrazide
  • R3 is H or C1-3 alkyl
  • R4 and R5 are independently selected from hydrogen, halogen and C1-3 alkyl
  • R6 is H or C1-3 alkyl
  • Z is selected from C, N , O and S
  • p is 1, 2 or 3
  • the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS.
  • Another aspect of the present invention provides a method for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula Ia or Ib, wherein each substituent is defined as described above, and the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS.
  • Another aspect of the present invention provides a compound represented by formula Ia or Ib for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, wherein each substituent is defined as described above, and the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS.
  • Another aspect of the present invention provides an ASC mutant protein, which comprises an amino acid residue mutation at at least one of I115, F163, W169 and L192, and the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2 (SEQ ID NO: 1).
  • Another aspect of the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, comprising identifying candidate drugs that interact with at least one of the amino acid residues I115, F163, W169 and L192 of the ASC protein.
  • FIG. 1 LND reduces inflammatory damage in EAE.
  • Body weight changes after EAE induction; n 12.
  • Representative H&E and Luxol Fast Blue (LFB) staining. Scale bar 100 ⁇ m.
  • LFD LND reduces inflammatory damage in EAE.
  • Body weight changes after EAE induction; n 10.
  • a, c, d, e, h, and i are unpaired t tests, and g and j are multiple unpaired t tests.
  • FIG. 1 LND inhibits inflammasome activation in vivo.
  • (c and d) ELISA analysis of IL-1 ⁇ (c) and IL-18 (d) in the serum of mice 4 hours after intraperitoneal injection of LPS (15 mg/kg), whether pretreated with LND or not, n 15. Data are expressed as mean ⁇ SEM. *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001; ****P ⁇ 0.0001; NS, not significant. Data were analyzed by one-way ANOVA and Tukey's test.
  • LND is a broad-spectrum inhibitor of the NLRP3 inflammasome.
  • (c and d) ELISA analysis of IL-1 ⁇ (c) and IL-18 (d) in the supernatant of BMDMs.
  • LPS-stimulated BMDMs were pretreated with or without LND (200 ⁇ M) for 30 min and then stimulated with nigericin, ATP, MSU, or imiquimod.
  • LND inhibits NLRP3 inflammasome activation independently of HK2.
  • Data are expressed as mean ⁇ SEM, *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001; ****P ⁇ 0.0001; NS, not significant. Data were analyzed by one-way ANOVA and Tukey's test.
  • LND prevents the formation of ASC specks.
  • LPS-stimulated BMDMs were treated with LND (0.2 mM) for 0.5 h and then stimulated with inflammasome activators (ATP (5 mM, 30 min), poly(dA:dT) (1 ⁇ g/ml, 8 h), MDP (200 ng/ml, 8 h), or flagellin (200 ng/ml, 8 h)).
  • IL-1 ⁇ in the supernatant of BMDMs was analyzed by ELISA. Data are presented as mean ⁇ SEM. *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001; ****P ⁇ 0.0001; NS, not significant. Data were analyzed by one-way ANOVA and Tukey's test.
  • FIG. 6 LND directly binds to ASC to inhibit NLRP3 assembly.
  • the docking model of ASC and LND was established using Ligand scout software. LND is shown as a stick in green. The CARD domain of ASC is shown in cartoon form in pink, while the interaction site is in orange. The yellow dashed line represents the hydrogen bond.
  • the graph showing the binding of LND to recombinant ASC protein was obtained by SPR analysis using Biacore. Different concentrations of LND are presented as an overlay.
  • C LPS-stimulated BMDMs were lysed with protein lysis buffer and incubated with LND overnight at 4°C.
  • DARTS detection was performed using pronase enzyme (20 ng/ ⁇ g protein) and analyzed by Western blot.
  • pronase enzyme (20 ng/ ⁇ g protein) and analyzed by Western blot.
  • halogen refers to fluorine, chlorine, bromine or iodine or a group thereof.
  • number of halogens is not limited, it can be any suitable number, such as monohalogen, dihalogen, trihalogen; when the position of the halogen is not limited, it can be any suitable position, for example, the halogenated phenyl can be halogenated at the ortho position, para position, meta position or a combination thereof.
  • alkyl refers to a saturated straight or branched hydrocarbon chain.
  • alkyl group having a specific number of carbon atoms the term includes the corresponding normal alkyl group and its various isomeric forms (if any).
  • an alkyl group having 3 carbon atoms C3 alkyl
  • C1-3 alkyl groups include methyl, ethyl, propyl, isopropyl.
  • C 1-3 alkylamino refers to an amino group substituted by a C 1-3 alkyl group, and may be an amino group substituted by one or two C 1-3 alkyl groups, for example, methylamino, dimethylamino, diethylamino, methylethylamino and the like.
  • halogenated C 1-3 alkyl refers to a C 1-3 alkyl group substituted by halogen, and may be a C 1-3 alkyl group substituted by one or more halogens simultaneously, such as fluoromethyl, difluoromethyl, trifluoromethyl and the like.
  • carboxyphenyl refers to a phenyl group substituted by a carboxyl group, and may be a phenyl group substituted by one or more carboxyl groups.
  • hydrozide refers to -C(O)-NH- NH2 .
  • terapéuticaally effective amount refers to an amount of a conjugate of the invention or composition thereof effective to produce some desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are within the scope of sound medical judgment and suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid or solvent encapsulating material, that participates in carrying or delivering the conjugate from one organ or part of the body to another organ or part of the body.
  • a pharmaceutically acceptable material such as a liquid or solid filler, diluent, excipient, manufacturing aid or solvent encapsulating material, that participates in carrying or delivering the conjugate from one organ or part of the body to another organ or part of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
  • treatment encompasses prevention, therapy, and cure.
  • the patient receiving such treatment is generally any animal in need, including primates (particularly humans) and other mammals such as horses, cattle, pigs, sheep, poultry, and pets.
  • diseases mediated by inflammasome activation based on the ASC-caspase-1 pathway refers to diseases mediated by abnormal inflammasome activation, which is based on the oligomerization of ASC to form ASC specks, which in turn recruits caspase-1 precursors and activates caspase-1.
  • Activated caspase-1 ultimately leads to the maturation and secretion of pro-inflammatory mediators IL-1 ⁇ and IL-18, and cleaves gasdermin D (GSDMD) to induce pyroptosis.
  • GDMD gasdermin D
  • Forma I includes Formula Ia and Formula Ib
  • Formula II includes Formula IIa and IIb
  • Formula III includes Formula IIIa and IIIb
  • Formula IV includes Formula IVa, IVb, and IVc.
  • One aspect of the present invention provides the use of a compound represented by Formula Ia or Ib or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide
  • R 3 is H or C 1-3 alkyl
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl
  • R 6 is H or C 1-3 alkyl
  • Z is selected from C, N, O and S
  • p is 1, 2 or 3
  • the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, maculopathy, benign prostatic hyperplasia and AIDS, preferably the disease is selected from asthma, allergic airway inflammation, gout, multiple sclerosis and sepsis.
  • R 1 is selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl;
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably carboxyl;
  • R 3 is H or C 1-3 alkyl, preferably hydrogen or methyl;
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably independently selected from hydrogen, methyl, fluorine and chlorine;
  • R 6 is H or C 1-3 alkyl, preferably H;
  • Z is selected from C, N, O and S, preferably C or N, more preferably C;
  • p is 1, 2 or 3, preferably 1.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl;
  • R 2 is carboxyl;
  • R 3 is H or C 1-3 alkyl, preferably hydrogen or methyl;
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably independently selected from hydrogen, methyl, fluorine and chlorine;
  • R 6 is H or C 1-3 alkyl, preferably H;
  • Z is selected from C, N, O and S, preferably C or N, more preferably C;
  • p is 1, 2 or 3, preferably 1.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl;
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably carboxyl;
  • R 3 is H or methyl;
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably independently selected from hydrogen, methyl, fluorine and chlorine;
  • R 6 is H or C 1-3 alkyl, preferably H;
  • Z is selected from C, N, O and S, preferably C or N, more preferably C;
  • p is 1, 2 or 3, preferably 1.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl;
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably carboxyl;
  • R 3 is H or C 1-3 alkyl, preferably hydrogen or methyl;
  • R 4 and R 5 are independently selected from hydrogen, methyl, fluorine and chlorine;
  • R 6 is H or C 1-3 alkyl, preferably H;
  • Z is selected from C, N, O and S, preferably C or N, more preferably C;
  • p is 1, 2 or 3, preferably 1.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl;
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably carboxyl;
  • R 3 is H or C 1-3 alkyl, preferably hydrogen or methyl;
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably independently selected from hydrogen, methyl, fluorine and chlorine;
  • R 6 is H;
  • Z is selected from C, N, O and S, preferably C or N, more preferably C;
  • p is 1, 2 or 3, preferably 1.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl;
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably carboxyl;
  • R 3 is H or C 1-3 alkyl, preferably hydrogen or methyl;
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably independently selected from hydrogen, methyl, fluorine and chlorine;
  • R 6 is H or C 1-3 alkyl, preferably H;
  • Z is C or N;
  • p is 1, 2 or 3, preferably 1.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl;
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably carboxyl;
  • R 3 is H or C 1-3 alkyl, preferably hydrogen or methyl;
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably independently selected from hydrogen, methyl, fluorine and chlorine;
  • R 6 is H or C 1-3 alkyl, preferably H;
  • Z is C or N;
  • p is 1.
  • R 1 is selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl;
  • R 2 is carboxyl;
  • R 3 is H or methyl;
  • R 4 and R 5 are independently selected from hydrogen, methyl, fluorine and chlorine;
  • R 6 is H;
  • Z is C;
  • p is 1.
  • a compound represented by Formula IIa or IIb or a pharmaceutically acceptable salt or ester thereof in the preparation of a drug for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably selected from methyl, fluorine and chlorine
  • the disease mediated by inflammasome activation based on the ASC-Caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS, preferably the disease is selected from: asthma, allergic airway inflammation, gout, multiple sclerosis and sepsis.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably selected from methyl, fluorine and chlorine, more preferably fluorine or chlorine
  • the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, maculopathy, benign prostatic hyperplasia and AIDS, preferably the disease is selected from: asthma, allergic airway inflammation, gout, multiple sclerosis and se
  • a compound represented by Formula IVa, IVb or IVc or a pharmaceutically acceptable salt or ester thereof in the preparation of a drug for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway.
  • R 1 is selected from hydrogen, halogen, C 1-3 alkyl, amino, C 1-3 alkylamino and halogenated C 1-3 alkyl
  • R 2 is selected from carboxyl, C 1-3 alkyl and hydrazide, preferably selected from hydrogen, fluorine, chlorine, iodine, methyl, ethyl, amino, dimethylamino, fluoromethyl, trifluoromethyl and difluoromethyl; more preferably selected from hydrogen, fluorine, chlorine and difluoromethyl
  • R 4 and R 5 are independently selected from hydrogen, halogen and C 1-3 alkyl, preferably selected from fluorine and chlorine, more preferably both are chlorine
  • the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, maculopathy, benign prostatic hyperplasia and AIDS, preferably the disease is selected from: asthma, allergic air
  • the compound of Formula I is selected from any of the following (the numbers in brackets represent PubChem CID):
  • the compound of formula I is 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid (ie, lonidamine, with a structural formula as shown in the following formula V) or a pharmaceutically acceptable salt or ester thereof.
  • the present invention provides the use of any compound of Formula I to Formula V as described above in the preparation of a medicament for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, wherein the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS.
  • the present invention provides use of any compound of Formula I to Formula V as described above in the preparation of a medicament for treating gout.
  • the present invention provides use of any one of the compounds of Formula I to Formula V as described above in the preparation of a medicament for treating multiple sclerosis.
  • the present invention provides use of any one of the compounds of Formula I to Formula V as described above in the preparation of a medicament for treating sepsis.
  • the present invention provides the use of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, wherein the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS.
  • the present invention provides the use of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, wherein the disease mediated by inflammasome activation based on the ASC-caspase-1 pathway is selected from asthma, allergic airway inflammation, gout, multiple sclerosis and sepsis.
  • the present invention provides the use of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for treating gout.
  • the present invention provides the use of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for treating multiple sclerosis.
  • the present invention provides the use of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for treating sepsis.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any compound represented by any one of Formula I to Formula V or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable composition includes one or more of the above-mentioned compounds in a therapeutically effective amount, used alone or formulated with one or more pharmaceutically acceptable carriers (additives), excipients and/or diluents.
  • the compounds according to the invention may be formulated for administration in any convenient way by analogy from other drugs for use in human or veterinary medicine.
  • Another aspect of the present invention provides a method for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, the method comprising administering to a subject in need thereof a therapeutically effective amount of any compound of any one of Formulas I to V described herein, wherein the disease is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia, and AIDS.
  • the disease is selected from asthma, allergic airway inflammation, gout, multiple sclerosis, and sepsis.
  • the disease is gout.
  • the disease is multiple sclerosis.
  • the disease is sepsis.
  • the compound of Formula I to Formula V is 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. Therefore, in some embodiments, the present invention provides a method for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, the method comprising administering a therapeutically effective amount of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof to a subject in need thereof, the disease is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS.
  • the present invention provides a method for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, the method comprising administering a therapeutically effective amount of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof to a subject in need thereof, the disease being selected from asthma, allergic airway inflammation, gout, multiple sclerosis and sepsis.
  • the present invention provides a method for treating multiple sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
  • the present invention provides a method for treating sepsis, comprising administering to a subject in need thereof a therapeutically effective amount of 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
  • Another aspect of the present invention provides any compound of any of Formula I to Formula V described herein for use in treating a disease mediated by inflammasome activation based on the ASC-Caspase-1 pathway, wherein the disease is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS.
  • the disease is selected from asthma, allergic airway inflammation, gout, multiple sclerosis and sepsis.
  • the disease is multiple sclerosis.
  • the disease is sepsis.
  • the compound of Formula I to Formula V is 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. Therefore, in some embodiments, the present invention provides 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, wherein the disease is not any of the following diseases: cancer, arthritis, acute central nervous system injury, Alzheimer's disease, infertility, macular degeneration, benign prostatic hyperplasia and AIDS.
  • the present invention provides 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof for treating a disease mediated by inflammasome activation based on the ASC-caspase-1 pathway, wherein the disease is selected from asthma, allergic airway inflammation, gout, multiple sclerosis and sepsis.
  • the present invention provides 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof for use in treating gout.
  • the present invention provides 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof for use in treating multiple sclerosis. In a preferred embodiment, the present invention provides 1-[(2,4-difluorophenyl)methyl]indazole-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof for use in treating sepsis.
  • Any compound of Formula I to Formula V provided by the present invention can be prepared by, for example, the method described in US20070015771A1 (Examples 8 to 39 thereof provide detailed preparation methods of indazole compounds), and the entirety of this patent document is incorporated herein by reference.
  • MS Multiple sclerosis
  • CNS central nervous system
  • the distribution, morphology, and signal performance of lesions on MRI are characteristic.
  • MS lesions are characterized by temporal multiple (DIT) and spatial multiple (DIS).
  • Clinically isolated syndrome refers to the first clinical attack, which often involves the unilateral optic nerve, spinal cord, brainstem, and can also involve the cerebral hemisphere. The lesions can be one or more. Not all patients progress to MS after the first attack, and CIS patients need close follow-up.
  • Remission-relapsing syndrome RRMS: In the early stages of the disease, patients often have repeated attacks, and most patients have complete relief of symptoms after the attack, which is called RRMS. 60-80% of patients will experience a stage of remission and relapse.
  • Secondary progressive syndrome After the patient experiences repeated attacks, the symptoms cannot be completely relieved, and the residual symptoms gradually accumulate and irreversible neurological disability occurs, that is, entering the progressive stage, so it is called secondary progressive syndrome.
  • Progressive relapsing syndrome PRMS
  • PRMS Progressive relapsing syndrome
  • PPMS Primary progressive syndrome
  • Acute MS is an acute variant of MS, which is aggressive, progresses rapidly in a short period of time, and often has multiple large lesions at the same time.
  • the present invention is intended to be used for any clinical classification of MS.
  • Sepsis also known as sepsis
  • sepsis-3 septic shock
  • SIRS systemic inflammatory response syndrome
  • Hyperuricemia causes gout, renal failure, etc.
  • the treatment of hyperuricemia mainly uses xanthine oxidase inhibitors such as allopurinol and febuxostat.
  • Gout attacks are caused by excessive uric acid in the blood and accumulation of uric acid crystals in the joints, which causes strong inflammation and onset of disease, accompanied by severe pain.
  • uric acid-lowering drugs There is a correlation between uric acid-lowering drugs and acute gout attacks. It is known that the sharp reduction of serum uric acid will produce short-term local precipitation of sodium urate crystals in cartilage and soft tissue, leading to acute gout attacks. That is, it is known that uric acid-lowering drugs in the past may induce gout attacks. Therefore, depending on the patient, it is sometimes necessary to stop treatment or change treatment guidelines due to gout attacks.
  • the present invention is expected to be used to treat gout.
  • Another aspect of the present invention provides an ASC mutant protein, which comprises an amino acid residue mutation at at least one of I115, F163, W169 and L192, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising an amino acid residue mutation at I115, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising an amino acid residue mutation at F163, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising an amino acid residue mutation at W169, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising an amino acid residue mutation at L192, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at I115 and F163, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at I115 and W169, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at I115 and L192, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at F163 and W169, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at F163 and L192, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at W169 and L192, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at I115, F163 and W169, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at I115, F163 and L192, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at F163, W169 and L192, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at I115, F163, W169 and L192, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the ASC mutant protein further comprises amino acid residue mutations at one or more of T166, L178 and S195.
  • the present invention provides an ASC mutant protein comprising amino acid residue mutations at I115, F163, T166, W169, L178, L192 and S195, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • the present invention provides an ASC mutant protein comprising I115A, F163A, T166A, W169A, L178A, L192A and S195A mutations, wherein the ASC mutant protein has a reduced number of ASC oligomers and/or spots relative to the wild-type protein, wherein the amino acid residue numbering is determined according to GenBank: BAA87339.2.
  • GenBank:BAA87339.2 The amino acid sequence of GenBank:BAA87339.2 is shown in SEQ ID NO:1, where the amino acid residues at the preferred mutation sites are shown in bold.
  • the present invention contemplates that the provided ASC mutant proteins can be used, for example, for disease treatment and drug screening.
  • a method for treating a disease mediated by activation of the ASC-caspase-1 inflammasome pathway is provided, the disease preferably being selected from asthma, allergic airway inflammation, gout, multiple sclerosis and sepsis, the method comprising administering a therapeutically effective amount of the ASC mutant protein or its encoding nucleic acid to a subject in need thereof.
  • the ASC mutant protein competes with the wild-type ASC protein to reduce the number of ASC oligomers and/or spots formed.
  • a method for treating a disease mediated by activation of the ASC-caspase-1 inflammasome pathway comprising administering a therapeutically effective amount of a base editor to a subject in need, the base editor causing a mutation in the ASC encoding gene, the mutation comprising at least one amino acid residue mutation at I115, F163, W169 and L192 to form any ASC mutant protein described in the present invention.
  • the base editor is, for example, an adenosine base editor (ABE) or a cytidine base editor (CBE).
  • the base editor is delivered to a cell via a vector such as a plasmid, a virus (eg, an adenovirus, an adeno-associated virus vector or a lentiviral vector).
  • a virus eg, an adenovirus, an adeno-associated virus vector or a lentiviral vector.
  • the disease mediated by activation of the ASC-caspase-1 inflammasome pathway is selected from asthma, allergic airway inflammation, gout, multiple sclerosis and sepsis.
  • Another aspect of the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying a candidate drug that interacts with at least one of the amino acid residues I115, F163, W169 and L192 of the ASC protein.
  • the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying a candidate drug that interacts with the I115 amino acid residue of the ASC protein.
  • the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying a candidate drug that interacts with the F163 amino acid residue of the ASC protein.
  • the present invention provides a method for computer-based screening of drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying a candidate drug that interacts with the W169 amino acid residue of the ASC protein.
  • the present invention provides a method for computer-based screening of drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying a candidate drug that interacts with the L192 amino acid residue of the ASC protein.
  • the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying candidate drugs that interact with the I115 and F163 amino acid residues of the ASC protein.
  • the present invention provides a method for computer-based screening of drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying candidate drugs that interact with the I115 and W169 amino acid residues of the ASC protein.
  • the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying candidate drugs that interact with the I115 and L192 amino acid residues of the ASC protein.
  • the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying candidate drugs that interact with the I115, F163, and W169 amino acid residues of the ASC protein.
  • the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying candidate drugs that interact with the I115, F163, and L192 amino acid residues of the ASC protein.
  • the present invention provides a method for computer-based screening of drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying candidate drugs that interact with the F163, W169, and L192 amino acid residues of the ASC protein.
  • the present invention provides a computer-based method for screening drugs for treating diseases mediated by activation of the ASC-caspase-1 inflammasome pathway, the method comprising identifying candidate drugs that interact with the I115, F163, W169 and L192 amino acid residues of the ASC protein.
  • the method includes identifying a candidate drug that also interacts with at least one of the amino acid residues T166, L178 and S195 of the ASC protein.
  • LND lonidamine
  • MS multiple sclerosis
  • HK2 hexokinase 2
  • LND is a broad-spectrum inflammasome inhibitor that directly targets ASC, providing a new therapeutic approach for the clinical treatment of inflammasome-driven diseases.
  • LND blocks inflammasome activation in an HK2-independent manner by directly targeting ASC and shows therapeutic effects in animal models of multiple inflammasome-related diseases, including MS and sepsis.
  • Anti-IL-1 ⁇ antibody was from RD Systems
  • anti-GSDMD anti-GSDMD
  • anti-NEK7 antibodies anti-NEK7 antibodies
  • anti-caspase-1 AG-20B-0042B
  • anti-ASC antibodies AG-25B-0006
  • anti- ⁇ -tubulin antibody ARG65693
  • LPS Erichia coli O111:B4; #L2630
  • ATP A6419
  • nigericin 481990
  • R-837 were obtained from Selleck.
  • MSU crystals (tlrl-msu), muramyld dipeptide (tlrl-mdp), flagellin from S. typhimurium (tlrl-stfla), and poly(dA:dT)/LyoVecTM were from Invivogen.
  • Anti-hexokinase 2 antibody (NBP2-02272) was from Novus.
  • Anti-NLRP3 antibody (15101) was from Cell Signaling Technology.
  • Goat anti-rabbit IgG (HRP) (arg65351), Donkey anti-goat IgG (HRP) (arg65352), and Goat anti-Mouse IgG antibodies (HRP) (arg65350) were all from Arigo.
  • Disuccinimidyl was purchased from Thermo Scientific.
  • mice C57BL/6J mice were obtained from Guangdong Medical Laboratory Animal Center (Guangzhou, China).
  • Conditional hexosidase II knockout mice B6.129P2(Cg)-Hk2tm1.1Uku/Kctt, HK2 CKO flox/flox
  • EMMA European Mouse Mutation Bank
  • B6J.B6n(Gg)-cx3cr1tm1.1(CRE)jung/j, Cx3cr1-Cre T) mice were obtained from Syy Biotech (Guangzhou) Co., Ltd. All animal experiments in this study were approved by the Institutional Animal Care and Use Committee and the Laboratory Animal Ethics Committee of Sun Yat-sen University (No. SYSU-IACUC-2022-B0070).
  • BMDMs were isolated from the bone marrow of 6-8 week old mice and cultured in DMEM medium containing 10% FBS and 20% supernatant of L929 cells (ATCC) for 7 to 8 days.
  • ATCC supernatant of L929 cells
  • HK2 in the mononuclear-macrophage cell line was selectively knocked out using CX3CR1-cre ⁇ HK2flox/flox mice, and primary BMDMs were then isolated from these HK2 knockout mice.
  • J774A.1 cells were from ATCC and cultured in DMEM containing 10% FBS.
  • BMDMs (5 ⁇ 10 5 cells/mL) and J774A.1 cells (3 ⁇ 10 5 cells/mL) were plated in 6-well plates and cultured overnight, and the medium was replaced with fresh DMEM the next morning. Then, the cells were induced with LPS (500 ng/mL) for 3 hours. After that, LND was added to the culture and incubated for 30 minutes.
  • LPS 500 ng/mL
  • the cells were stimulated with ATP (5 mM) for 30 minutes, MSU (150 ⁇ g/mL), Iiquimod (100 ⁇ M) and nigericin (10 ⁇ M) for 4 hours, poly (dA: dT) (2 ⁇ g/mL, 6 hours), MDP (500 ng/mL, 6 hours) and flagellin (1 ⁇ g/mL, 6 hours).
  • ATP 5 mM
  • MSU 150 ⁇ g/mL
  • Iiquimod 100 ⁇ M
  • nigericin 10 ⁇ M
  • poly (dA: dT) (2 ⁇ g/mL, 6 hours)
  • MDP 500 ng/mL, 6 hours
  • flagellin 1 ⁇ g/mL, 6 hours
  • LPS-induced sepsis model 8-week-old male C57BL/6 mice were intraperitoneally injected with LND (40 mg/kg and 60 mg/kg) or solvent control ( ⁇ -cyclodextrin) 0.5 hours before intraperitoneal injection of LPS (15 mg/kg) (Sigma-Aldrich, L2630). Four hours later, the mice were euthanized, and the levels of IL-1 and IL-18 in the serum were measured using ELISA kits according to the manufacturer's instructions.
  • 0 no symptoms
  • 1 loss of tail rigidity
  • 2 unsteady gait
  • 3 hind limb paralysis
  • 4 forelimb paralysis
  • 5 moribund or dead. If the score was between two points, a grading of 0.5 points was used.
  • ASC oligomerization detection BMDMs were seeded in 6-well plates, washed with ice-cold PBS, and 500 ⁇ L of ice-cold buffer (20 mM HEPES-KOH, pH 7.5, 150 mM KCl, 1% NP40, protease inhibitors) was added. The cells were lysed at 4°C for 30 min, and 50 ⁇ L of lysate was taken out for Western blot detection. Then, the remaining lysate was centrifuged at 2500 ⁇ g for 10 min at 4°C. The pellet was resuspended in 500 ⁇ L of ice-cold PBS.
  • succinimidyl ester (Thermo Fisher A39267) was added to the resuspended pellet and incubated with rotation at room temperature for 30 min. Then, centrifuged at 2500 ⁇ g for 10 min at 4°C. The supernatant was removed and the cross-linked pellet was resuspended in 30 ⁇ L of Laemmli buffer. The samples were boiled at 100°C for 10 min and analyzed by Western blot.
  • ELISA method Analyze mouse IL-1 ⁇ (LIANKE BIOTECH, EK201B/3), IL-18 (LIANKE BIOTECH, EK218) and TNF- ⁇ (LIANKE BIOTECH, EK282/3) in cell culture supernatant and serum according to the reagent manufacturer's instructions.
  • IP Immunoprecipitation
  • Immunohistochemical staining Brain and spinal cord samples were analyzed according to the manufacturer's instructions of the immunohistochemical (IHC) staining kit (Abcam, ab80436, Cambridge, MA, USA). Briefly, after deparaffinization and hydration, the sections were placed in 3% hydrogen peroxide for 15 minutes and antigen retrieval was performed for 20 minutes before cooling to room temperature. The sections were stained with H&E, Nissl, or LFB, respectively. The samples were incubated with the indicated primary antibodies overnight at 4°C in antibody diluent containing background reducing agent (DAKO, S3022, Santa Clara, CA, USA). Then, after washing three times with PBS, the sections were stained with diaminobenzidine (DAB) substrate-color-changing agent mixture and hematoxylin in sequence.
  • DAB diaminobenzidine
  • Immunofluorescence staining During tissue sectioning, the brain and spinal cord were routinely isolated and fixed. Then, the samples were embedded in paraffin and cut into 5 ⁇ m thick sections. After deparaffinization and hydration, the sections were subjected to antigen retrieval for 20 min and cooled to room temperature. The samples were incubated with the designated primary antibodies at 4 °C overnight in antibody diluent with background elimination reagent (DAKO, S3022, Santa Clara, CA, USA). The samples were washed three times with PBS and incubated with the designated fluorescence-conjugated secondary antibodies (Molecular Probes, Thermo Fisher Scientific, Rockford, IL, USA) for 1 h.
  • DAKO antibody diluent with background elimination reagent
  • Flow cytometry To analyze the infiltrating immune cells of the central nervous system, the brain tissue and spinal cord of MOG 35-55 immunized mice were ground with a tissue homogenizer to form a single cell suspension, which was filtered through a 300 mesh filter. After centrifugation, the single cell suspension was resuspended with 37% percoll and centrifuged for 30 minutes at 1000 ⁇ g, room temperature, minimum acceleration setting and no brake. Mononuclear cells were separated from the lowest layer. The cells were suspended in PBS containing 1% FBS. Washed three times and stained with cell surface marker antibodies for flow cytometric analysis. The following antibodies were used.
  • CD45-BV510 (BD, 563891), CD4-FITC (BioLegend, 100406), CD8-Alexa Fluor 700 (BD, 557959), and CD11b-BV421 (BioLegend, 101236).
  • Flow cytometric analysis was performed by flow cytometer (CytoFLEX, Beckman Coulter). Cell debris and dead cells were excluded based on forward and side scatter and Fixable Viability Stain 780 (BD, 565388).
  • siRNA-mediated gene interference in BMDMs Small interfering RNA was purchased from RiboBio (Guangzhou RiboBio Co., Ltd.). RNA interference was performed using Lipofectamine TM RNAiMAX (Invitrogen, 13778) according to the manufacturer's instructions. RNA interference was performed on cells that reached 60-70% confluence. Samples were collected 48 hours after RNA interference and Western blot or real-time PCR were performed as described above. The sequences of siRNA are as follows.
  • DARTS assay DARTS was performed according to published protocols. BMDMs (5 ⁇ 10 5 cells/mL) were plated in 10 cm dishes and cultured overnight, and the medium was replaced with fresh DMEM the next morning. Then, cells were induced with LPS for 4 h and lysed with M-PER (Thermo, 78501) lysis buffer. The lysate was centrifuged at 12,000 ⁇ g for 10 min at 4 °C, and the protein concentration was determined by BCA protein concentration assay. The lysate was incubated with LND overnight at 4 °C. 80 ⁇ g of protein lysate was used for each reaction.
  • M-PER Thermo, 78501
  • pronase enzyme Sigma, PRON-RO
  • 20 ng of pronase enzyme Sigma, PRON-RO
  • the digestion was terminated by adding 20 ⁇ protease inhibitor, and the samples were incubated on ice for 10 min.
  • 5 ⁇ SDS-PAGE loading buffer was added to the samples to reach a final concentration of 1 ⁇ SDS-PAGE buffer. Protein samples were analyzed by Western blot.
  • Transmission electron microscopy Purified expressed ASC protein samples (6 ⁇ M) were added with TEV enzyme (6 UI) and different concentrations of LND and incubated overnight at 4 °C. A drop of 10 ⁇ l of sample was placed on a clean Parafilm and a mesh copper pure carbon coated grid was floated on top for 10 min. Then, the grid was transferred and contrasted with 1% uranyl acetate for 5 min. Excess fluid was removed and allowed to dry before examination using a transmission electron microscope FEI Tecnai G2 Spirit (ThermoFisher Scientific Company, OR, USA). All images were acquired using Radius software and a Xarosa digital camera (EMSIS GmbH, Weg, Germany).
  • SPR Surface plasmon resonance analysis: The experiments were performed in a Biacore T100. Recombinant human ASC protein (Zeye Biotechnology) was immobilized on a CM5 sensor chip (BR100530, Cytiva). LND was dissolved in basic running buffer (PBS with 1% DMSO) and injected into the flow cell at a flow rate of 5 ⁇ L/min at 25 °C. The sensor chip was washed with basic running buffer between each concentration. ASC protein was immobilized in different channels of the same chip, and the response values obtained by injecting blank basic running buffer in the same way were used as controls. The kinetic parameters and affinity constants of the interaction were calculated using the Biacore T100 evaluation software.
  • Example 1 reduces inflammatory damage in experimental autoimmune encephalomyelitis (EAE).
  • Example 2 inhibits the activation of inflammasomes.
  • Inflammasomes are the main sensors of sterile inflammatory signals and a key trigger of inflammatory responses.
  • LND could inhibit inflammasome activation in vivo.
  • the spinal cord of EAE mice described above we found that the increased levels of GSDMD and caspase-1 were significantly reduced after LND treatment ( Figures 2a and 2b). This suggests that LND prevented inflammasome activation in the central nervous system tissues of EAE mice.
  • LPS lipopolysaccharide
  • Example 3 LND inhibited NLRP3 inflammasome activation induced by different agonists.
  • the NLRP3 inflammasome can be activated by other danger-associated molecular patterns, such as nigericin and monosodium urate (MSU), which are dependent on potassium ion efflux.
  • MSU monosodium urate
  • Treatment with LND inhibited caspase-1 cleavage and IL-1 ⁇ secretion triggered by nigericin and MSU ( Figures 3o and 3p).
  • imiquimod an NLRP3 inflammasome activator that is independent of potassium ion efflux, also inhibited imiquimod-induced caspase-1 and IL-1 ⁇ activation ( Figures 3o and 3p).
  • Example 4 inhibits NLRP3 inflammasome activation independently of HK2.
  • LND inhibits glycolysis by inhibiting the activity of HK2.
  • LND has other targets, including voltage-dependent anion channel (VDAC), mitochondrial pyruvate carrier (MPC) and monocarboxylate transporters (MCT) and succinate dehydrogenase (SDH).
  • VDAC voltage-dependent anion channel
  • MCT mitochondrial pyruvate carrier
  • MCT monocarboxylate transporters
  • SDH succinate dehydrogenase
  • siRNA-mediated interference with HK2 did not reduce caspase-1 cleavage and IL-1 ⁇ production in BMDMs ( Figures 4c and 4d) and J1774A.1 cells ( Figures 4e and 4f).
  • LPS- and ATP-induced NLRP3 inflammasome activation was comparable in BMDMs from wild-type (WT) mice and HK2 knockout mice ( Figure 4g), and LND still attenuated NLRP3 activation in BMDMs from HK2 knockout mice ( Figures 4h and 4i). This result suggests that LND inhibits NLRP3 inflammasome activation independent of HK2.
  • Example 5 selectively blocks oligomerization of ASC.
  • LND inhibits inflammasome activation.
  • a series of upstream events such as potassium ion efflux and the generation of reactive oxygen species (ROS)
  • ROS reactive oxygen species
  • LND can inhibit NLRP3 inflammasome activation induced by different activators that are dependent or independent of potassium ion efflux ( Figure 3).
  • LND did not inhibit the generation of ROS when inhibiting inflammasome activation ( Figure 5a).
  • NIMA-related kinase 7 (NEK7) has been identified as an essential component of the NLRP3 inflammasome, and the interaction between NEK7 and NLRP3 has been shown to be critical for NLRP3 oligomerization and inflammasome assembly.
  • LND had no effect on the binding between NEK7 and NLRP3 in BMDMs ( Figure 5b).
  • ASC-mediated ligation of NLRP3 and caspase-1 is another key step in inflammasome assembly.
  • LND did not block the interaction between NLRP3 and ASC ( Figure 5c), but inhibited the binding between ASC and caspase-1 ( Figure 5d).

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Abstract

La présente invention concerne l'utilisation d'un composé tel que représenté par la formule I ou d'un sel ou ester pharmaceutiquement acceptable de celui-ci dans la préparation d'un médicament pour le traitement de maladies médiées par l'activation de l'inflammasome sur la base de la voie ASC-caspase-1. En particulier, le composé de la présente invention est de préférence la lonidamine, et est utilisé pour traiter la goutte, la sclérose en plaques ou la septicémie.
PCT/CN2023/130416 2022-11-08 2023-11-08 Utilisation d'un composé indazole dans le traitement de maladies médiées par l'activation de l'inflammasome Ceased WO2024099346A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110114351A (zh) * 2016-12-12 2019-08-09 维托尔股份有限公司 Mct4的杂环抑制剂
WO2022061008A2 (fr) * 2020-09-17 2022-03-24 Escient Pharmaceuticals, Inc. Modulateurs du récepteur x4 de la protéine g associée à mas et produits et procédés associés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110114351A (zh) * 2016-12-12 2019-08-09 维托尔股份有限公司 Mct4的杂环抑制剂
WO2022061008A2 (fr) * 2020-09-17 2022-03-24 Escient Pharmaceuticals, Inc. Modulateurs du récepteur x4 de la protéine g associée à mas et produits et procédés associés

Non-Patent Citations (3)

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Title
CHEN CHEN, ZHOU YUWEI; NING XINPENG; LI SHENGLONG; XUE DONGDONG; WEI CAILV; ZHU ZHU; SHENG LONGXIANG; LU BINGZHENG; LI YUAN; YE XI: "Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases", JOURNAL OF NEUROINFLAMMATION, BIOMED CENTRAL LTD., LONDON, GB, vol. 19, no. 1, GB , XP093170266, ISSN: 1742-2094, DOI: 10.1186/s12974-022-02682-w *
LI YANG, FU TIAN-MIN; LU ALVIN; WITT KRISTEN; RUAN JIANBIN; SHEN CHEN; WU HAO: "Cryo-EM structures of ASC and NLRC4 CARD filaments reveal a unified mechanism of nucleation and activation of caspase-1", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 115, no. 43, 23 October 2018 (2018-10-23), pages 10845 - 10852, XP093170274, ISSN: 0027-8424, DOI: 10.1073/pnas.1810524115 *
SORIANO-TERUEL PAULA M, GARCÍA‑LAÍNEZ GUILLERMO; MARCO-SALVADOR MARÍA; PARDO JULIÁN; ARIAS MAYKEL; DEFORD CHRISTIAN; MERFORT IRMGA: "Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases", CELL DEATH & DISEASE, NATURE PUBLISHING GROUP, GB, vol. 12, no. 12, GB , XP093170272, ISSN: 2041-4889, DOI: 10.1038/s41419-021-04420-1 *

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