WO2023283977A1 - Utilisation d'une préparation pour inhiber ou bloquer l'interaction entre faah et nlrp3 - Google Patents

Utilisation d'une préparation pour inhiber ou bloquer l'interaction entre faah et nlrp3 Download PDF

Info

Publication number
WO2023283977A1
WO2023283977A1 PCT/CN2021/107643 CN2021107643W WO2023283977A1 WO 2023283977 A1 WO2023283977 A1 WO 2023283977A1 CN 2021107643 W CN2021107643 W CN 2021107643W WO 2023283977 A1 WO2023283977 A1 WO 2023283977A1
Authority
WO
WIPO (PCT)
Prior art keywords
nlrp3
faah
interaction
protein
preparation
Prior art date
Application number
PCT/CN2021/107643
Other languages
English (en)
Chinese (zh)
Inventor
温龙平
张云娇
朱阳阳
张�浩
Original Assignee
华南理工大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 华南理工大学 filed Critical 华南理工大学
Publication of WO2023283977A1 publication Critical patent/WO2023283977A1/fr

Links

Images

Classifications

    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present invention relates to the use of agents for inhibiting or blocking the interaction between FAAH and NLRP3.
  • the inflammasome is a multiprotein signaling platform that drives inflammatory responses in response to exogenous or endogenous danger signals.
  • the NLRP3 inflammasome has been the most studied.
  • the NLRP3 inflammasome also contains an adapter (ASC; also known as PYCARD) and an effector (Caspase 1, Caspase 1).
  • ASC adapter
  • Caspase 1 caspase 1 is cleaved and activated, leading to the activation and release of the pro-inflammatory cytokines IL-1 ⁇ and IL-18, as well as pyroptosis.
  • cryopyrin-associated periodic syndromes including familial cold autoinflammatory syndrome (FCAS), Moore-Weiss syndrome syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID, also known as chronic infantile neurocutaneous joint syndrome or CINCA).
  • NLRP3 inflammasome Although much has been learned about the NLRP3 inflammasome, many unanswered questions remain. One of the questions is whether there is a mechanism for maintaining the stability of NLRP3 protein prior to inflammasome activation. As dysregulated NLRP3 inflammasome activity drives the development of many inflammatory, metabolic, neurodegenerative and autoimmune diseases, controlling NLRP3 inflammasome activity is critical. According to this principle, the NLRP3 protein in cells is usually maintained at a very low level, which is not sufficient for activation.
  • Toll-like receptors recognize danger-associated molecular patterns (DAMPS) or pathogen-associated molecular patterns (PAMPS), triggering the synthesis of large amounts of NLRP3 protein, but these proteins remain inactive non-assembled state.
  • DAMPS danger-associated molecular patterns
  • PAMPS pathogen-associated molecular patterns
  • mitochondrial antiviral signal MAVS
  • cardiolipin mitochondrial protein
  • mitochondrial protein mitochondrial protein (mitochondrion)
  • STING can all anchor NLRP3 to mitochondria or endoplasmic reticulum, but the anchoring effect of these molecules on NLRP3 protein may be It is limited to some special situations, such as during viral infection, or only works on some NLRP3 proteins.
  • Fatty acid amide hydrolase is a membrane protein that plays a key regulatory role in the endocannabinoid system. It is mainly located in the endoplasmic reticulum and mitochondria in cells. Endogenous signaling lipids such as endogenous cannabinoids (AEA) are inactivated to regulate various physiological processes such as pain, feeding, blood pressure, mood, sleep, etc. Whether FAAH affects NLRP3 protein stability or inflammasome activation has not been reported yet.
  • FAAH Fatty acid amide hydrolase
  • the present invention provides the use of a preparation for inhibiting or blocking the interaction between FAAH and NLRP3.
  • the technical solution adopted: the use of a preparation that inhibits or blocks the interaction between FAAH and NLRP3 in screening drugs for treating diseases caused by NLRP3 inflammasomes.
  • the present invention provides the application of the preparation for inhibiting or blocking the interaction between FAAH and NLRP3 in screening the medicine for treating diseases caused by NLRP3 protein mutation.
  • the present invention provides the use of the preparation for inhibiting or blocking the interaction between FAAH and NLRP3 in the preparation of medicines for treating diseases caused by NLRP3 inflammasomes.
  • the invention provides the use of the preparation for inhibiting or blocking the interaction between FAAH and NLRP3 in the preparation of medicines for treating diseases caused by NLRP3 protein mutations.
  • the diseases caused by NLRP3 inflammasomes are type II diabetes, gout, Alzheimer's disease, atherosclerosis, Parkinson's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, asthma, Chronic obstructive pulmonary disease, nephritis, enteritis, hepatitis.
  • the disease caused by mutation of NLRP3 protein is cryopyrin-related periodic syndrome.
  • the diseases caused by NLRP3 protein mutations are Familial Cold Autoinflammatory Syndrome (FCAS), Moore-Weiss Syndrome (MWS) and Chronic Infantile Neurocutaneous Arthritis Syndrome (CINCA).
  • FCAS Familial Cold Autoinflammatory Syndrome
  • MFS Moore-Weiss Syndrome
  • CINCA Chronic Infantile Neurocutaneous Arthritis Syndrome
  • the agent for inhibiting or blocking the interaction between FAAH and NLRP3 includes 3'-carbamoylbiphenyl-3-ylcyclohexylcarbamate, biochanin A, N-benzyl palmitate Amide, N-(4-chloro-3-pyridyl)-4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-1-piperazinecarboxamide , 4-morpholinyl-1,2,5-thiadiazol-3-yl cyclooctyl (methyl) carbamate and N-3-pyridazinyl-4-[[3-[[5- At least one of (trifluoromethyl)-2-pyridyl]oxy]phenyl]methylene]-1-piperidinecarboxamides.
  • the agent for inhibiting or blocking the interaction between FAAH and NLRP3 includes 3'-carbamoylbiphenyl-3-ylcyclohexylcarbamate.
  • the agent for inhibiting or blocking the interaction between FAAH and NLRP3 includes a polypeptide having an amino acid sequence as shown in SEQ ID NO:1.
  • the invention adopts the preparation that blocks the interaction between FAAH and NLRP3, so that the NLRP3 protein is degraded in an unstable state, so as to treat diseases related to NLRP3 inflammasomes.
  • the NLRP3 protein produced in cells after the first signal stimulation is in an inherently unstable state, and its stability depends on the interaction with the membrane enzyme FAAH, thereby being anchored to the mitochondrial and endoplasmic reticulum membranes ;Blocking the interaction between NLRP3 and FAAH can dissociate NLRP3 protein from mitochondria and endoplasmic reticulum membrane, and then cause K48 ubiquitination of NLRP3 protein through the action of E3 ubiquitin protein ligase (CHIP), and finally through E3 ubiquitin
  • CHIP E3 ubiquitin protein ligase
  • NBR1 protein ligase
  • the present invention uses inhibitors or blocks the interaction between FAAH and NLRP3 The interacting agents are effective against diseases caused by both mutated and non-mutated NLRP3 proteins.
  • Figure 1 shows that NLRP3 in macrophages is basically not expressed under non-stimulation conditions.
  • the first signal stimulation leads to high expression but no inflammasome activation ability, and it is only activated to produce inflammatory factors after the second signal stimulation.
  • Figure 2 shows that the knockout of FAAH leads to the reduction of NLRP3 inflammasome activation in animal models, and the levels of IL-1 ⁇ and TNF-a in the peritoneal cavity of WT, FAAH+/- and FAAH-/-BMDM mice were detected by ELISA.
  • Serum Serum.
  • Figure 3 shows that FAAH knockdown leads to NLRP3 protein degradation.
  • Panel a Western blot analysis of NLRP3, FAAH and GAPDH in WT, FAAH+/- and FAAH-/- BMDMs.
  • b Immunoblot analysis of NLRP3 and GAPDH in LPS-primed (mock) WT and FAAH-/-BMDM with or without co-treatment of CHX.
  • Panel c Western blot analysis of NLRP3, FAAH and GAPDH in LPS-primed (mock) WT and FAAH-/- BMDM with or without co-treatment with nigericin.
  • FIG. 4 shows that FAAH knockdown leads to reduced activation of NLRP3 inflammasome in cells.
  • Figure 5 shows that NLRP3 protein degradation by FAAH knockdown is dependent on autophagy rather than the proteasome pathway
  • panel a in LPS-triggered (mock) FAAH-/-BMDM with or without co-treatment with 3MA, CQ or Wortmannin, Immunoblot analysis of NLRP3 and GAPDH.
  • b Immunoblot analysis of NLRP3 and GAPDH in LPS-primed FAAH-/-BMDMs (mock) that had been transfected with scrambled (scrambke) or ATG5-specific siRNA.
  • Figure 6 shows that FAAH knockdown leads to increased K48 ubiquitination of NLRP3 protein, which is required for NLRP3 protein degradation.
  • Untreated or LPS-triggered WT and FAAH- Cell lysates of /-BMDMs were then immunoblotted with K48-Ub, K63-Ub or NLRP3 antibodies.
  • Figure 7 shows that the NLRP3 protein caused by FAAH knockout requires the E3 ligase CHIP protein.
  • the protein extracted from BMDM and FAAH-/-BMDMs was immunoprecipitated with NLRP3-specific antibody, and then immunoprecipitated with NLRP3, NBR1 and CHIP antibodies blot.
  • b Immunoblot analysis of NLRP3, CHIP and GAPDH in LPS-primed FAAH-/- BMDM transfected with CHIP-specific siRNA.
  • Figure 8 shows that the degradation of NLRP3 protein caused by FAAH knockdown requires the selective receptor protein NBR1 protein, NLRP3, NBR1 and GAPDH in FAAH-/-BMDM induced by LPS transfected with NBR1-specific siRNA were analyzed by immunoblotting. Input refers to unsedimented cell lysate.
  • Figure 9 shows that FAAH interacts with and stabilizes NLRP3 proteins
  • panel a cell lysates from LPS-primed BMDMs were immunoprecipitated with isotype- or NLRP3-specific antibodies, followed by immunoblot analysis for NLRP3 and FAAH.
  • b Cell lysates of untreated or LPS-primed (mock) BMDMs were immunoprecipitated with FAAH-specific antibodies, followed by immunoblot analysis for NLRP3 and FAAH.
  • c Proximity ligation assay (PLA) of NLRP3-FAAH interaction in LPS-triggered WT, FAAH+/- and FAAH-/- BMDMs; scale bar, 20 ⁇ m.
  • PLA Proximity ligation assay
  • Figure 10 shows the domain mapping analysis of the interaction between FAAH and NLRP3, and the AS-1 short peptide was designed accordingly.
  • Panel a, b HEK293T cells were co-transfected with Flag-tagged NLRP3 construct and HA-tagged FAAH construct. Immunoblot analysis of HA and Flag proteins in cell lysates immunoprecipitated with anti-Flag antibody.
  • Figure 11 shows that mutant NLRP3 interacts with FAAH in cells.
  • Panel a HEK293T cells were co-transfected with Flag-tagged wild-type and three mutant NLRP3 constructs and HA-tagged FAAH constructs. Immunoblot analysis of HA and Flag proteins in cell lysates immunoprecipitated with anti-Flag antibodies.
  • b Immunoprecipitation of LPS-primed NLRP3-R258W knock-in BMDMs with isotype- or NLRP3-specific antibodies, followed by immunoblot analysis of NLRP3-R258W and FAAH.
  • c PLA of NLRP3-R258W-FAAH interaction in LPS-stimulated NLRP3-R258W knock-in BMDMs; scale bar, 20 ⁇ m.
  • Figure 12 shows that FAAH knockout leads to degradation of mutant NLRP3 protein.
  • Figure 13 shows that knockout of FAAH leads to reduced activation of the mutant NLRP3 inflammasome in animal models and amelioration of CAPS disease symptoms.
  • a Photographs of WT, NLRP3-R258W, FAAH+/-R258W and FAAH-/-R258WBMDM mice at 12 weeks of age.
  • b Axillary lymph nodes, spleen and liver of WT, NLRP3-R258W, FAAH+/-R258W and FAAH-/-R258WBMDM mice.
  • Figure 14 shows that FAAH knockdown results in reduced activation of the mutant NLRP3 inflammasome in cells.
  • lysis means precipitation.
  • Figure 15 shows that knockdown of FAAH leads to the dissociation of NLRP3 protein from mitochondria and endoplasmic reticulum membranes, panel a, in LPS-induced WT and FAAH-/-BMDMs, obtained from the cytosolic and membrane fractions of cell lysates Western blot analysis of NLRP3, CRT, TOM20 and GAPDH.
  • b Cell lysates of WT and FAAH-/-BMDMs were immunoprecipitated with anti-NLRP3 antibody, followed by immunoblotting analysis for NLRP3, CRT, and TOM20. Cells were unstimulated (control) or stimulated with LPS for 3 hours.
  • c and d NLRP3-TOM20 interaction in PLA (c) and NLRP3-CRT interaction (d) in LPS-induced WT and FAAH-/-BMDM; scale bar, 20 ⁇ m.
  • Figure 16 shows that mutant NLRP3 interacts with mitochondria and endoplasmic reticulum membranes in cells with normal FAAH expression.
  • a and b NLRP3-TOM20 interaction in PLA (a) and NLRP3-CRT interaction (b) in LPS-induced WT, FAAH+/-R258W and FAAH-/-R258W BMDM; scale bar, 20 ⁇ m.
  • Fig. 17 Degradation effect of different FAAH inhibitors on NLRP3 protein.
  • JZL195, URB597, LY2183240, PF3845, Biochanin A, N-Benzyllinolenamide, Carprofen, BIA10-2474, FAAH-IN-2, N-Benzylpalmitamide, 1-monomyristin, JNJ-42165279, JZL-184, JZP-430, PF- 04457845, SA47 these 14 kinds of FAAH inhibitors were tested, among them URB597, Biochanin A, N-Benzylpalmitamide, JNJ-42165279, JZP-430, PF-04457845 these 6 kinds have significant activity, this is by NLRP3 at the concentration of 40uM Defined by the ability to reduce protein levels by more than 30%.
  • Figure 18 shows that URB597 causes NLRP3 protein to dissociate from FAAH.
  • Figure 19 shows that URB597 results in reduced NLRP3 inflammasome activation in cells.
  • a IL-1 ⁇ and cleaved caspase-1 (p20) in culture supernatant (SN) and Pro-Caspase-1 in cell lysate (lysed) and Pro-IL-1 ⁇ immunoblot analysis.
  • BMDM were stimulated with LPS for 3 hours, then treated with the indicated concentrations of URB597 for 3 hours, and then challenged with Nigericin for 30 minutes.
  • Figure 20 shows that the degradation of NLRP3 protein induced by URB597 is achieved through the autophagy pathway.
  • Figure 21 shows that URB597 causes mutant NLRP3 protein degradation in mouse BMDM cells.
  • Figure 22 shows that URB597 causes dissociation of NLRP3 protein from FAAH in CAPS patient monocytes.
  • Cells were stimulated with LPS for 3 hours and then treated with 40 ⁇ M URB597 for another 3 hours.
  • Figure 23 shows that URB597 results in reduced NLRP3 inflammasome activation in CAPS patient monocytes.
  • NS not significant.
  • b and c PBMCs from patients 2(b) and 3(c), respectively, were stimulated with LPS for 3 hours and then treated with 40 ⁇ M URB597 for 3 hours.
  • N2 is the normal mother of patient 2
  • Figure 24 shows that AS-1 peptide causes separation of NLRP3 protein from FAAH.
  • Figure 25 shows that AS-1 peptide causes NLRP3 protein degradation.
  • Figure 26 shows that AS-1 peptide results in reduced NLRP3 inflammasome activation in cells.
  • BMDM were stimulated with LPS for 3 hours, then treated with different concentrations of AS-1 short peptide for 3 hours, and then stimulated with Nigericin for 30 minutes.
  • Biochanin A is the following formula (V):
  • N-Benzyl-(9Z,12Z,15Z)-octadecatrienamide N-Benzyllinolenamide
  • N-benzyl palmitamide N-Benzylpalmitamide
  • N-3-pyridazinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridyl]oxy]phenyl]methylene]-1-piperidinecarboxamide (PF- 04457845) has the following structural formula (XV):
  • FAAH-/- mice had reduced FAAH enzyme activity and, under AEA challenge, exhibited enhanced cold response and reduced pain sensitivity in both tail immersion and hot plate tests. FAAH-/- mice also exhibited low reproductive capacity, whereas FAAH+/- mice reproduced normally. IL-1 ⁇ release triggered by nigericycin following LPS priming in BMDMs carrying loss of FAAH heterozygosity (FAAH+/-) and homozygosity (FAAH-/-) compared to BMDMs derived from wild-type mice about 50% and 70% lower, respectively. A significant decrease in IL-1 ⁇ secretion was also observed in FAAH-/-BMDM after ATP and MSU challenge. In addition, loss of FAAH also reduced IL-18 release and death of pyrocytes.
  • a second FAAH knockout mouse created by another company through a similar but slightly different strategy, also exhibited Protein X in BMDM but not in major tissues including brain, liver and kidney.
  • Kupffer cells isolated from FAAH-/- mice do not express protein X, show no detectable levels of NLRP3 protein after LPS initiation (Fig. 3c), and IL-1 release is reduced by nearly 90% after nigermycin challenge (Fig. 4), showing that FAAH loss has a greater effect on NLRP3 in Kupffer cells than in BMDM.
  • a second FAAH gene has been identified in humans and many other species, but not in mice and rats. The identity of protein X and its possible role in NLRP3 stability and activation are still being investigated.
  • NLRP3 is degraded by selective autophagy
  • NLRP3 exhibited enhanced K48 ubiquitination, but not K63 ubiquitination, in FAAH-/- BMDMs compared to FAAH+/+ BMDMs (Fig. 6).
  • Dopamine has been reported to induce ubiquitination-dependent autophagic degradation of NLRP3 in macrophages, and two of the many known E3 ligases, MARCH7 and CHIP, associate with NLRP3 after dopamine treatment (but only MARCH7 is responsible for dopamine-induced NLRP3 degradation, a result we were able to replicate).
  • CHIP but not MARCH7 binds to NLRP3 in FAAH-/-BMDM (Fig. 7a).
  • FAAH interacts with and stabilizes NLRP3 protein
  • NLRP3 was also found to be associated with FAAH in the mouse macrophage cell line J774A.1.
  • the interaction between NLRP3 and FAAH is highly selective because FAAH does not interact with other inflammasome-associated proteins including ASC, caspase 1, NEK7, NLRC4 and AIM2, whereas NLRP3 does not interact with Monoacylglycerol lipase (MAGL), a hydrolase in the endocannabinoid system, interacts.
  • MAGL Monoacylglycerol lipase
  • the NACHT domain of NLRP3 spanning the region between aa 91 and aa 710 is both necessary and sufficient for the interaction with FAAH
  • the region between aa 150 and aa 265 of FAAH is critical for the interaction with NLRP3, as the aa 1 to 265 fragment of FAAH interacts with full-length NLRP3, whereas the aa fragment from aa 1 to 150 does not effect (Figure 10a, Figure 10b).
  • AS amidase signature
  • FAAH also interacts with and stabilizes NLRP3-R258W
  • NLRP3-R258W strongly interacts with FAAH in BMDMs derived from NLRP3-R258W knock-in mice ( Figures 11b and 11c).
  • BMDMs initiated by LPS the levels of NLRP3-R258W were comparable to wild-type NLRP3, suggesting that FAAH has a similar ability to stabilize wild-type and mutant NLRP3 in these cells.
  • NLRP3-R258W mice exhibited a wrinkled coat, hair loss, smaller body mass and body weight, and severe skin inflammation, but FAAH+/-R258W mice showed significant improvement in all of these aspects (representative Sexual photos are shown in Figure 13a). NLRP3-R258W mice also showed enlargement of axillary lymph nodes, spleen and liver, whereas those excised from FAAH+/- R258W mice were significantly smaller (but still significantly larger than WT mice; Figure 13b).
  • FAAH anchors NLRP3 to mitochondria and ER membranes
  • NLRP3 an intracellular membrane protein known to be associated with ER and mitochondria
  • FAAH an intracellular membrane protein known to be associated with ER and mitochondria
  • Most of the NLRP3 protein is present in the membrane fraction that contains mitochondria but not ER, suggesting that mitochondria may be more involved in the cellular localization of NLRP3 than ER.
  • deletion of FAAH resulted in an increase in the cytosolic fraction of NLRP3 protein, whereas conversely a decrease in the membrane fraction (Fig. 15a).
  • URB597 The most active compound URB597 among the tested inhibitors was selected for further study.
  • URB597 also dose-dependently reduced NLRP3 protein levels in mouse peritoneal macrophages and two other macrophage cell lines that we have studied.
  • URB597 increased autophagy levels in mouse BMDM in a dose-dependent manner, and autophagy inhibitors but not proteasome inhibitors significantly abolished the NLRP3-lowering effect of URB597 ( Figures 5a, 5b, and 5c).
  • URB597 treatment resulted in enhanced K48 ubiquitination of NLRP3 and promoted the binding of CHIP and NBR1 to NLRP3, suggesting the same mechanism of selective autophagy.
  • URB597 disrupted the endogenous NLRP3-FAAH interaction in mouse BMDM ( Figure 18).
  • dopamine did not disrupt the NLRP3-FAAH interaction.
  • URB597 As expected from its superior ability to trigger NLRP3 degradation, URB597 dose-dependently inhibited IL-1 ⁇ and cleavage triggered by NLRP3-specific stimuli including Nigeria, ATP, MSU and alum in LPS-primed mice Secretion of caspase 1.
  • BMDM Fig. 19a and Fig. 19b.
  • URB597 also inhibited nigericin-induced apoptosis.
  • 3-MA abolished the NLRP3 degradation effect of URB597 (Fig. 20), able to "rescue" NLRP3 inflammasome activation inhibited by URB597.
  • project P1 P2 P3 refer to unit C-reactive protein, CRP 68 49 96 ⁇ 8 mg/L white blood cells, WBC 31.7 13.1 20.0 4.0-10.0 10 9 /L Neutrophils, NEUT# 23.0 8.5 8.4 0.7-4.6 10 9 /L Lymphocytes, LYMPH# 8.0 3.8 10.0 1.48-7.8 10 9 /L Hemoglobin, Hgb 89 90 81 110-160 g/L Platelets, Plt 824 579 558 100-400 10 9 /L Erythrocyte sedimentation rate, ESR twenty two 46 40 0-20 mm/h
  • PBMCs isolated from Patient 1 a 2-year-old girl diagnosed with FCAS, in which There is an A354T mutation in the NLRP3 gene.
  • PBMCs from patient 1 showed increased both spontaneous and LPS-triggered release of IL-1 ⁇ compared to CAPS-free PBMCs obtained from her mother (Fig. 23a).
  • URB597 was able to reduce both spontaneous and LPS-triggered IL-1 ⁇ release, with approximately 50% inhibition observed in LPS-triggered IL-1 ⁇ release.
  • MCC950 was not effective in this patient.
  • Enhanced spontaneous and LPS-triggered IL-1 ⁇ release was also observed in PBMCs isolated from two other patients, a 3-year-old girl diagnosed with FCAS with the T350M mutation, and a 7-month-old boy Diagnosed with CINCA with the M408T mutation in the NLRP3 gene.
  • URB597 again effectively inhibited both spontaneous and LPS-triggered IL-1 ⁇ release, with 40% and 60% inhibition of LPS-triggered IL-1 ⁇ release for patients 2 and 3, respectively (Fig. 23b and 23c).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Pulmonology (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biochemistry (AREA)

Abstract

Utilisation d'une préparation pour inhiber ou bloquer une interaction entre FAAH et NLRP3. Au moyen de la préparation pour inhiber ou bloquer l'interaction entre FAAH et NLRP3, une protéine NLRP3 se trouve dans un état instable et est dégradée, traitant ainsi des maladies inflammatoires associées à l'activation des inflammasomes NLRP3. La préparation utilisée peut également traiter efficacement des maladies inflammatoires associées aux mutations de protéine NLRP3.
PCT/CN2021/107643 2021-07-15 2021-07-21 Utilisation d'une préparation pour inhiber ou bloquer l'interaction entre faah et nlrp3 WO2023283977A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110800301.2A CN115616216A (zh) 2021-07-15 2021-07-15 抑制或阻断faah与nlrp3之间相互作用的制剂的用途
CN202110800301.2 2021-07-15

Publications (1)

Publication Number Publication Date
WO2023283977A1 true WO2023283977A1 (fr) 2023-01-19

Family

ID=84855745

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/107643 WO2023283977A1 (fr) 2021-07-15 2021-07-21 Utilisation d'une préparation pour inhiber ou bloquer l'interaction entre faah et nlrp3

Country Status (2)

Country Link
CN (1) CN115616216A (fr)
WO (1) WO2023283977A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12091413B2 (en) 2020-05-08 2024-09-17 Halia Therapeutics, Inc. Inhibitors of NEK7 kinase

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103006631A (zh) * 2012-12-28 2013-04-03 武汉华士特工业生物技术开发有限公司 N-苄基脂肪酰胺类化合物在制备神经保护药物中的应用
WO2014004676A1 (fr) * 2012-06-26 2014-01-03 Ironwood Pharmaceuticals, Inc. Utilisation des inhibiteurs de faah comme agents neuroprotecteurs du snc
CN103502237A (zh) * 2010-12-22 2014-01-08 硬木药品公司 Faah抑制剂
CN108349867A (zh) * 2015-08-17 2018-07-31 安成生物科技股份有限公司 用于抑制asc的表达、nlrp3的表达和/或nlrp3炎性复合体的形成的双醋瑞因或其类似物
US20190380980A1 (en) * 2015-05-20 2019-12-19 Dublin City University A Method For Treating Peripheral Inflammatory Disease
CN111094243A (zh) * 2017-07-24 2020-05-01 诺华炎症研究公司 用于治疗与nlrp活性相关的病症的化合物和组合物
CN111356680A (zh) * 2017-07-31 2020-06-30 诺瑟拉有限公司 Nlrp3炎性体的选择性抑制剂
WO2020208249A1 (fr) * 2019-04-12 2020-10-15 Inflazome Limited Inhibition de l'inflammasome nlrp3

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103502237A (zh) * 2010-12-22 2014-01-08 硬木药品公司 Faah抑制剂
WO2014004676A1 (fr) * 2012-06-26 2014-01-03 Ironwood Pharmaceuticals, Inc. Utilisation des inhibiteurs de faah comme agents neuroprotecteurs du snc
CN103006631A (zh) * 2012-12-28 2013-04-03 武汉华士特工业生物技术开发有限公司 N-苄基脂肪酰胺类化合物在制备神经保护药物中的应用
US20190380980A1 (en) * 2015-05-20 2019-12-19 Dublin City University A Method For Treating Peripheral Inflammatory Disease
CN108349867A (zh) * 2015-08-17 2018-07-31 安成生物科技股份有限公司 用于抑制asc的表达、nlrp3的表达和/或nlrp3炎性复合体的形成的双醋瑞因或其类似物
CN111094243A (zh) * 2017-07-24 2020-05-01 诺华炎症研究公司 用于治疗与nlrp活性相关的病症的化合物和组合物
CN111356680A (zh) * 2017-07-31 2020-06-30 诺瑟拉有限公司 Nlrp3炎性体的选择性抑制剂
WO2020208249A1 (fr) * 2019-04-12 2020-10-15 Inflazome Limited Inhibition de l'inflammasome nlrp3

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SU SHAO-HUA, WU YI-FANG, LIN QI, WANG DA-PENG, HAI JIAN: "URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion", JOURNAL OF NEUROINFLAMMATION, BIOMED CENTRAL LTD., LONDON, GB, vol. 16, no. 1, 1 December 2019 (2019-12-01), GB , pages 260 - 15, XP093023769, ISSN: 1742-2094, DOI: 10.1186/s12974-019-1668-0 *
WANG JUN, YANG LI; LI WEIZU; YIN YANYAN: "Regulatory effect of corticosterone preconditioning on lipopolysaccharide-activated NLRP3 inflammasome in microglial cells and protective effect of chicitein A", ACTA NEUROPHARMACOLOGICA, vol. 7, no. 3, 1 June 2017 (2017-06-01), pages 47 - 47, XP093023778, ISSN: 2095-1396 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12091413B2 (en) 2020-05-08 2024-09-17 Halia Therapeutics, Inc. Inhibitors of NEK7 kinase

Also Published As

Publication number Publication date
CN115616216A (zh) 2023-01-17

Similar Documents

Publication Publication Date Title
Bambouskova et al. Itaconate confers tolerance to late NLRP3 inflammasome activation
Yekkirala et al. Breaking barriers to novel analgesic drug development
Orlowski et al. Multiple cathepsins promote pro–IL-1β synthesis and NLRP3-mediated IL-1β activation
Gasse et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis
Katsnelson et al. NLRP3 inflammasome signaling is activated by low-level lysosome disruption but inhibited by extensive lysosome disruption: roles for K+ efflux and Ca2+ influx
Mantuano et al. The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein
Groß et al. Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1
Orlowski et al. Frontline science: multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation
TWI779805B (zh) 補體活性之調節劑
Sanz et al. Nimodipine inhibits IL‐1β release stimulated by amyloid β from microglia
Impellizzeri et al. Effect of fasudil, a selective inhibitor of Rho kinase activity, in the secondary injury associated with the experimental model of spinal cord trauma
Schiffers et al. The transient receptor potential channel vanilloid 1 is critical in innate airway epithelial responses to protease allergens
Shen et al. The histone deacetylase inhibitor belinostat ameliorates experimental autoimmune encephalomyelitis in mice by inhibiting TLR2/MyD88 and HDAC3/NF-κB p65-mediated neuroinflammation
US11376229B2 (en) Method of treating or preventing neurodegeneration
CA3084043A1 (fr) Modulateurs de l'activite du complement
Jäger et al. The NLRP3-inflammasome-caspase-1 pathway is upregulated in idiopathic pulmonary fibrosis and acute exacerbations and is inducible by apoptotic A549 cells
Fiorucci et al. A NO‐releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway THIS ARTICLE HAS BEEN RETRACTED
Rose et al. Transglutaminase 2 limits murine peritoneal acute gout‐like inflammation by regulating macrophage clearance of apoptotic neutrophils
TW201836634A (zh) 補體活性之調節劑
Jendzjowsky et al. PKCε stimulation of TRPV1 orchestrates carotid body responses to asthmakines
Li et al. GABAergic inhibition regulated pain sensitization through STEP61 signaling in spinal dorsal horn of mice
Sibilano et al. Modulation of FcεRI-dependent mast cell response by OX40L via Fyn, PI3K, and RhoA
WO2023283977A1 (fr) Utilisation d'une préparation pour inhiber ou bloquer l'interaction entre faah et nlrp3
Du et al. The pore-forming subunit Kir6. 1 of the K-ATP channel negatively regulates the NLRP3 inflammasome to control insulin resistance by interacting with NLRP3
Lai et al. SIRPα1-SHP2 interaction regulates complete freund adjuvant–induced inflammatory pain via Src-Dependent GluN2B phosphorylation in rats

Legal Events

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

Ref document number: 21949757

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21949757

Country of ref document: EP

Kind code of ref document: A1