WO2008132458A1 - Compositions utiles dans la modulation de réponses immunitaires et le traitement ou la prévention de réponses inflammatoires et procédés apparentés - Google Patents

Compositions utiles dans la modulation de réponses immunitaires et le traitement ou la prévention de réponses inflammatoires et procédés apparentés Download PDF

Info

Publication number
WO2008132458A1
WO2008132458A1 PCT/GB2008/001460 GB2008001460W WO2008132458A1 WO 2008132458 A1 WO2008132458 A1 WO 2008132458A1 GB 2008001460 W GB2008001460 W GB 2008001460W WO 2008132458 A1 WO2008132458 A1 WO 2008132458A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
methyl
formula
ethylene
covalent bond
Prior art date
Application number
PCT/GB2008/001460
Other languages
English (en)
Other versions
WO2008132458A8 (fr
Inventor
Grahame James Mckenzie
Bryn Shaun Hardwick
Dirk Rolf Gewert
Original Assignee
Inion Limited
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 Inion Limited filed Critical Inion Limited
Publication of WO2008132458A1 publication Critical patent/WO2008132458A1/fr
Publication of WO2008132458A8 publication Critical patent/WO2008132458A8/fr

Links

Classifications

    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to compounds and compositions containing such compounds for use in therapy and to numerous related applications thereof. More particularly, the invention relates to the modulation of inflammatory and immune responses and also the treatment of inflammation. Particularly, although not exclusively, the invention relates to a group of substituted piperidones, pyrrolidones, lactams, caprolactams and for the modulation of immune responses, and also for treatment of inflammatory conditions such as arteriosclerosis, atherosclerosis, arthritis, psoriasis and ankylosing spondylitis.
  • Immune responses to antigen challenge are an important component of the human or animal body's defences against a range of insults . These insults include infectious agents such as bacteria, viruses, parasites and prions. Antigen dependent immune responses also play a role in the defence against cancer or the response to allergens . Modulation of such antigen dependent immune responses represents a potential therapeutic avenue in conditions or pathologies associated with each of the above scenarios .
  • Inflammation is also part of the human or animal body's response to a range of insults. However, inflammation can sometimes be undesirable or harmful. Inflammatory conditions cause substantial mortality and morbidity in the population at large. Inflammatory conditions can be acute or chronic. Chronic inflammatory conditions include arteriosclerosis, atherosclerosis, arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis and ankylosing spondylitis. Examples of acute inflammatory conditions include septic shock and anaphylactic shock amongst others .
  • KLF2 Kruppel-like transcription factor 2
  • HGNC Hugo Gene Nomenclature Committee
  • LKLF Lung Kruppel-Like Factor
  • KLF2 has also attracted interest as a more general modulator of inflammation and localised vascular thrombosis.
  • KLF2 has been considered to be an atheroprotective factor during stress to the vascular endothelium, the key barrier in determining vascular homeostasis .
  • Forced expression of KLF2 drives endothelial transcriptional programs which regulate inflammation, thrombosis haemostasis, vascular tone, and blood vessel development.
  • KLF2 is a master regulator of atheroprotective transcriptional programs (3) .
  • KLF2 plays a role in stem cells (5) . Therefore molecules that regulate KLF2 can be used in the field of stem cells. Such uses for example include, stem cell therapies such as the therapeutic use of cardiomyocytes for treatment of damage following myocardial infarction.
  • the present invention is based around the identification of new modulators of KLF2 levels in cells.
  • the present invention is therefore concerned with the provision of new active agents for the modulation of immune responses and/or for the modulation (for example treatment or prevention) of inflammatory conditions or diseases.
  • the compounds, compositions, uses and methods described herein may thus be useful in circumstances under which it is desirable to modulate one or more immune responses alone, modulate inflammation alone (for example to treat or prevent one or more inflammatory conditions or diseases) , or the combination of both modulation of immune responses and inflammation together.
  • the present invention provides use of a compound of the formula:
  • X is a covalent bond, methylene, or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl in the manufacture of a medicament for use in the modulation of an immune response and/or the treatment or prevention of an inflammatory condition.
  • the compound for use in the manufacture of a medicament as described above has X as a covalent bond and R as methyl.
  • This compound is referred to as N-methyl-pyrrolidone, (NMP) .
  • the compound for use in the manufacture of a medicament as described above has X as a covalent bond and R as vinyl. This compound is referred to as l-vinyl-2-pyrrolidone .
  • the compound for use in the manufacture of a medicament as described above has X as methylene and R as methyl. This compound is referred to as 1-methyl-2-piperidone .
  • the compound for use in the manufacture of a medicament as described above has X as ethylene and R as methyl. This compound is referred to as N-methylcaprolactam.
  • the compound for use in the manufacture of a medicament as described above has X ethylene and R as acetyl. This compound is referred to as N-acetylcaprolactam.
  • modulation of an immune response it is meant that a response to an antigen is altered relative to the response to that antigen when the compound of the invention is absent. Generally, the “modulation” comprises an elevated or improved immune response to the particular antigen. In a specific embodiment the immune response may be modulated such that an antigen dependent response to a vaccine is enhanced or boosted.
  • the term "inflammatory condition" is used herein to refer to unwanted or pathological inflammation.
  • the inflammatory condition may be selected from any disease that involves undesirable or pathological inflammation of any bodily tissue.
  • the inflammatory condition to be treated with the medicament according to the present invention is selected from the group comprising acute inflammation, chronic inflammation, septic shock, arteriosclerosis, atherosclerosis, arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis or ankylosing spondylitis .
  • the medicaments and compounds of the present invention are particularly suitable for the treatment of arteriosclerosis and atherosclerosis. Accordingly, preferred medicaments of the invention are for use in the treatment of arteriosclerosis and atherosclerosis.
  • the medicaments of the invention may be formulated for any suitable dosage regimen. Particularly preferred embodiments are medicaments formulated for systemic administration or for localised administration.
  • the medicaments of the invention may contain any number of pharmaceutically acceptable excipients.
  • excipients used in the art are generally well known and may include fillers, lubricants, colours, flavours, wetting agents, solvents, buffering agents, preservatives and the like.
  • the medicaments may contain one or more additional pharmaceutical compounds .
  • the medicaments of the invention contain at least one additional anti-inflammatory drug and/or anti- atherosclerotic drug. Any suitable anti-inflammatory and/or anti-atherosclerotic may be utilised.
  • the at least one additional anti- inflammatory drug comprises a non-steroidal antiinflammatory drug (NSAID) .
  • NSAID non-steroidal antiinflammatory drug
  • the medicaments comprise at least one compound according to the present invention together with ibuprofen and/or aspirin.
  • the present invention provides a compound of the formula :
  • X is a covalent bond, methylene or ethylene,- and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl.
  • the compound of the present invention has X as a covalent bond and R as methyl (N- methyl-pyrrolidone, NMP) .
  • the compound of the present invention has X as a covalent bond and R as vinyl (1-vinyl- 2-pyrrolidone) .
  • the compound of the present invention has X as methylene and R as methyl (1-methyl-2- piperidone) .
  • the compound of the present invention has X as ethylene and R as methyl (N- methylcaprolactam) . In a preferred embodiment, the compound of the present invention has X as ethylene and R as acetyl (N- acetylcaprolactam) .
  • the medicament may be in any suitable form for use in therapy.
  • the description of medicaments and pharmaceutical compositions provided herein therefore applies mutatis mutandis to this aspect of the invention.
  • the present invention provides a method of treatment for modulating an immune response, and/or of treating or preventing an inflammatory condition.
  • modulation of an immune response may be achieved by the adjuvant activity of compounds of the inventions, i.e. enhancing said immune response, such as boosting antigen- dependent immune responses when co-administered with a vaccine.
  • medicaments of the invention may additionally comprise one or more vaccines.
  • treatment is meant at least improvement, preferably cure of the condition in question.
  • Treatment may also include prophylactic, i.e. preventative treatment aimed at preventing the occurrence or severity of the condition in a subject judged to be at risk of developing a condition to be treated.
  • X is a covalent bond and R as methyl (N-methyl-pyrrolidone, NMP) ; X - S -
  • X is a covalent bond and R as vinyl (l-vinyl-2-pyrrolidone) ; or X is methylene and R as methyl (1-methyl-2-piperidone) ; X is ethylene and R is methyl (N-methylcaprolactam) ; or X is ethylene and R is acetyl (N-acetylcaprolactam) .
  • the method may comprise simultaneous, separate, or sequential administration of one or more compounds of the invention and of a vaccine .
  • an immune response to the vaccine may be modulated.
  • Said modulation may be enhancement or boosting of the immune response.
  • the methods of the invention are also applicable to the treatment of one or more inflammatory conditions .
  • the term "inflammatory condition" is used herein to refer to unwanted or pathological inflammation.
  • the inflammatory condition may be selected from any disease that involves undesirable or pathological inflammation of any bodily tissue.
  • the inflammatory condition to be treated by the method according to the present invention is selected from the group comprising acute inflammation, chronic inflammation, septic shock, arteriosclerosis, atherosclerosis, arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis or ankylosing spondylitis.
  • the invention relates to a pharmaceutical composition comprising at least one compound according to the present invention.
  • the medicaments and pharmaceutical compositions of the present invention may be administered systemically or locally. This is applicable to both the use and method aspects of the invention equally.
  • Systemic administration may be by any form of systemic administration known, for example, orally, intravenously or intraperitoneally.
  • Local administration may be by any form of local administration known, for example topically.
  • the pharmaceutical composition includes at least one pharmaceutically acceptable excipient.
  • compositions and medicaments of the invention for use in the methods of the invention may take the form of a tablet, capsule, injectable solution, implantable slow release matrix or device or any other suitable form.
  • compositions and medicaments according to the invention may also take the form of a powder for direct inhalation, a suppository, or a solution which may be suitable for transdermal application.
  • one medicament according to the invention may simply comprise a solution of the active agents in a suitable solvent, for example dimethyl sulphoxide .
  • compositions and medicaments according to the invention may be manufactured using any suitable method.
  • the compositions may be dry milled and mixed prior to tableting and the composition may therefore necessarily contain other pharmaceutically acceptable excipients such as a lubricant selected from the group comprising calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and combinations thereof, a binding agent selected from the group comprising hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and a polyvinyl pyrrolidone (PVP) .
  • a lubricant selected from the group comprising calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and combinations thereof
  • a binding agent selected from the group comprising hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and a polyvinyl pyrrolidone (P
  • compositions and medicaments according to the invention may contain any pharmaceutically acceptable excipients such as binders, fillers, pigments, disintegrating agents, lubricants, wetting agents, buffers and other excipients conventionally used in the pharmaceutical and chemical fields.
  • excipients for use in the compositions and medicaments of the present invention are microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, and titanium dioxide.
  • compositions or medicaments of the invention may be administered with any inert diluent or with an edible carrier. They may be incorporated directly into food or beverages making up part of the patient ' s diet .
  • the compositions or medicaments of the invention may be formulated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspension syrups, wafers, and the like.
  • the tablets, troches, pills, capsules and the like may contain those excipients already mentioned and in some cases may also contain sweetening agents, such as sucrose, glucose, aspartame or saccharin, flavouring agents such as essential oils of mint, peppermint, spearmint or any other suitable flavouring.
  • sweetening agents such as sucrose, glucose, aspartame or saccharin
  • flavouring agents such as essential oils of mint, peppermint, spearmint or any other suitable flavouring.
  • the dosage unit may additionally contain a liquid carrier such as an oil or buffered aqueous solution.
  • Medicaments and compositions of the invention may also be formulated with phospholipids or fatty acids or other synthetic nanoparticles as carriers.
  • Medicaments and compositions of the invention may take the form of formulations for parenteral administration and may include sterile aqueous solutions or dispersions, and sterile powders for the preparation of sterile, injectable solutions or dispersions.
  • the solutions or dispersions may also contain buffers, diluents, and other suitable additives that may be designed to promote the cellular uptake of the active agents in the composition, for example, liposomes.
  • compositions for topical administration may be especially useful for localized treatment.
  • Formulations for topical treatment include ointments, sprays, gels, suspensions, lotions, creams, and the like.
  • Formulations for topical administration may include known carrier materials such as isopropanol, glycerol, paraffin, stearyl alcohol, polyethylene glycol, and the like.
  • Medicaments and compositions of the invention may also include a known chemical absorption promoter.
  • Absorption promoters include, for example, trichloroethanol, trifluoroethanol, and certain alcohols and mixtures thereof (according to GB 1,001, 949 to Meyer and GB 1,464, 975 to AstraLakemedel, these references are hereby incorporated in their entirety) .
  • Medicaments and compositions of the invention suitable for rectal or vaginal administration may be presented as a suppository, which may include one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound .
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound .
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate .
  • a subject in need of treatment may be an individual diagnosed with an inflammatory condition, or a patient wanting to prevent or delay the onset of a inflammatory condition, for example, someone with a family history of arteriosclerosis, atherosclerosis, arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis or ankylosing spondylitis.
  • the medicament compositions may be simply taken as a prophylactic.
  • the terms “treating” and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediaton of damage.
  • the present method of "treating" an inflammatory condition encompasses both prevention of the disorder and treatment of the disorder in a clinically symptomatic individual.
  • pharmaceutically acceptable carrier includes a material which is not biologically or otherwise undesirable. Such a material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • the pharmaceutical composition of the invention further comprises at least one additional pharmaceutical compound.
  • the at least one additional pharmaceutical compound may for example be a vaccine or vaccine composition, an anti- inflammatory compound or drug, or an anti-atherosclerotic or anti-arteriosclerotic compound or drug.
  • Such combination of further pharmaceutical compounds with the compounds of the invention may allow for additive or potentially synergistic effects between the compounds of the invention and the further pharmaceutical compounds.
  • the combination of active ingredients may allow for a simpler treatment or dosage regime, for example by reducing the number of individual tablets or injections that are required to be taken by the subject.
  • the pharmaceutical composition comprises one of the compounds according to the present invention along with an at least one additional pharmaceutical compound.
  • the at least one additional pharmaceutical compounds may be an anti- inflammatory drug and/or anti-atherosclerotic drug. Any- suitable ani-inflammatory and/or anti-atherosclerotic may be used.
  • the at least one additional antiinflammatory drug comprises a non-steroidal antiinflammatory drug (NSAID) .
  • NSAID non-steroidal antiinflammatory drug
  • the medicaments comprise at least one compound according to the present invention together with ibuprofen and/or aspirin.
  • the ibuprofen and/or aspirin is present in an amount of less than 250 mg, more preferably less than 100 mg daily.
  • the medicament is formulated so that the daily amounts may be incorporated into a single tablet.
  • the present invention also provides one or more compounds of the invention and an additional pharmaceutical compound for simultaneous, separate or sequential use in the modulation of an immune response and/or the treatment or prevention of an inflammatory condition.
  • the compound of the invention and the additional pharmaceutical compound may be administered in combination, but in a variety of different forms or routes .
  • the skilled person would be able to determine the optimum dosage, route of administration and relative temporal interval between administration of said compounds of the invention and said additional pharmaceutical compounds.
  • the present invention relates to a coating composition for a medical device wherein the coating composition comprises a therapeutically effective amount of at least one compound of the invention.
  • the coating compositions of the present invention may therefore find use in providing coatings for medical devices wherein said medical devices may or may not themselves comprise one or more compounds of the invention.
  • therapeutically effective amount is meant an amount of the compound sufficient to give rise to the desired therapeutic effect.
  • therapeutically effective amount is an amount sufficient to modulate an immune response or to treat or prevent an inflammatory condition.
  • the present invention relates to a medical device comprising at least one compound according to the present invention.
  • the medical device may be manufactured separately and then have the compounds of the invention applied to one or more surfaces .
  • compounds of the invention may be, for example, blended with the ingredients used to make the medical device. It is envisaged that medical devices comprising compounds according to the present invention may comprise said compounds in a slow release formulation, thereby providing continuous delivery of the compound of the invention over time.
  • the compounds of the invention may be provided in the form of a medicament or pharmaceutical composition as described in detail herein.
  • the medical device may comprise any medical device, in particular a medical device, which is introduced into a subject.
  • the introduction of the device may be by- implantation or insertion for example .
  • the device may be inside the subject for any length of time, dependent upon the particular device which is being utilised.
  • the device is any of a catheter, stent, guidewire, sensor, ventricular assist device (VAD) , graft, valve such as an aortic valve, pacemaker, artificial joint, or infusion system/pump.
  • the subject is most preferably a human subject.
  • the device comprises, consists essentially of or consists of a stent which has had a compound according to the present invention coated on at least one surface thereof such that in use a subject will be exposed to the at least one compound of the invention.
  • the device may be biodegradable, for example a biodegradable stent.
  • the coating comprising the compound of the invention may be biodegradable.
  • the compound of the invention is adsorbed onto a suitable coating, such as a known hydromer coating for example.
  • a suitable coating such as a known hydromer coating for example.
  • Any suitable (biocompatible) coating for a medical device may be utilised.
  • the incorporation of one or more of the compounds of the invention into a stable coating facilitates a prolonged, controlled release of the compound or compounds of the invention from the surface on dissolution of the biodegradable polymers .
  • a co-polymer blend is utilised.
  • suitable polymers into which the compounds of the invention may be (non-covalently) incorporated include, but are not limited to, poly (hexano-6-lactone) , poly (ethylene- co-vinyl acetate) (EVA), poly (ethylene oxide) (PEO), polyvinylpyrollidone, poly (tetrafluoroe-thylene) (PTFE) , poly (dimethylsilo-xane) , polypropylene, poly (ethyleneterephthalate) (PET) , polyamides (nylons) , poly (ether urethane) (e.g.
  • Pellethane poly (ether urethane urea) (e.g. Biomer) , low density polyethylene (LDPE), high density polyethylene (HDPE) , polysulfones, polyvinylchloride (PVC), poly (2-hydroxyethylmethacrylate (PHEMA) and polylactide and blends thereof such as poly (hexano- 6- lactone) /polyactide blends and EVA/PEO blends.
  • LDPE low density polyethylene
  • HDPE high density polyethylene
  • PVC polyvinylchloride
  • PHEMA poly (2-hydroxyethylmethacrylate
  • Co-polymers such as these offer a range of drug release properties and are clinically acceptable, and may be readily optimized for the desired release kinetics of the compounds of the invention.
  • Polymer coatings may be prepared by any suitable method, such as by standard dip-coating methods. Suitable polymer- blends may be dissolved in an appropriate solvent. Examples of a solvent which may be utilised to produce coatings according to the invention include dichloromethane and methylethylketone .
  • the dosage of the compositions of the invention depends on the individual patients and the disorder to be treated.
  • An exemplary single dose of a composition of the invention is within the range of about 0.001 to about 4 mg. However, smaller dosages may be sufficient, and larger doses may also be required.
  • the polymer which incorporates one or more compounds of the invention also incorporates polyethylene glycol (PEG) molecules/monomers therein.
  • PEG is a well known hydrophilic molecule which has many uses in the coatings of the invention. Various forms of PEG are commercially available.
  • Suitable monomers include polyethylene glycol acrylates, including momo- methoxy triethylene glycol mono (meth) acrylate, mono-methoxy tetraethylene glycol mono (meth) acrylate and polyethylene glycol mono (meth) acrylate .
  • the invention relates to a medical device when made according to an appropriate method of the invention.
  • the present invention also relates to a method of assessing suitability of an individual for treatment with a compound according to the present invention, the method comprising: a) in a test sample taken from the individual, determining the level of KLF2 expression, wherein a low level of KLF2 expression is indicative of the suitability of the individual to treatment with the compound, and/or b) in a test sample taken from the individual, determining the level of KLF2 expression before and after treatment with the compound, wherein an increase in KLF2 expression as a result of treatment with the compound is indicative of the suitability of the individual to treatment with the compound; and/or c) in a test sample taken from the individual, determining the DNA sequence upstream of a KLF2 gene present in the test sample and comparing the DNA sequence obtained with the sequence of any one of SEQ ID NOs. 1-5, wherein a level of sequence identity of at least 90% is indicative of the suitability of the individual to treatment with a compound as defined above.
  • upstream is meant the portion of the nucleic acid molecule to be found in a 5 ' direction from the proposed transcriptional start site.
  • This portion of the molecule may be 10 000 base pairs in length, or more preferably 9000, 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, 500, 482, 400, 300, 200, 150, 111, 100, 63, 50, 25, 10 or 8 base pairs in length.
  • the level of sequence identity may be 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.
  • sequence identity refers to the relationship between sequences at the nucleotide level.
  • the expression "% identical” is determined by comparing optimally aligned sequences, e.g. two or more, over a comparison window wherein the portion of the sequence in the comparison window may comprise insertions or deletions as compared to the reference sequence for optimal alignment of the sequences. The reference sequence does not comprise insertions or deletions.
  • the reference window is chosen from between at least 10 contiguous nucleotides to about 50, about 100 or to about 150 nucleotides, preferably between about 50 and 150 nucleotides. "% identity" is then calculated by determining the number of nucleotides that are identical between the sequences in the window, dividing the number of identical nucleotides by the number of nucleotides in the window and multiplying by 100.
  • the invention also relates to a method of assessing the effect of treatment with a compound according to the present invention, the method comprising: a) in a test sample taken from the individual before treatment of the individual with a compound of the invention determining the level of KLF2 expression, b) in a test sample taken from the individual after treatment of the individual with a compound of the invention determining the level of KLF2 expression, c) comparing the levels of KLF2 expression obtained in a) and b) wherein an increase in KLF2 expression as a result of treatment of the individual with the compound is indicative of an effect on KLF2 expression by treatment of the individual with a compound of the invention.
  • the effect on KLF2 expression is indicative of a beneficial or positive effect on treatment of the individual.
  • the method further comprises comparing the levels of KLF2 expression in further samples that have been taken from the subject at time points subsequent to the time points where steps a) and b) are carried out .
  • the differences in the levels of expression must be statistically significant in order to provide a reliable test for assessing the suitability of an individual for treatment with a compound of the invention, or for assessing the effect of treatment with a compound of the invention.
  • a low level of expression is meant a level of expression that is, statistically speaking, lower than that expected or observed in a 'normal' sample or individual.
  • any method for determining the relative expression level of a gene, or whether the expression level of a gene is significantly increased or decreased may be utilised. Such methods are well known in the art and routinely employed. For example, statistical analyses may be performed using an analysis of variance test. A typical P value for use in such a method would be P values of ⁇ 0.05 when determining whether the relative expression is statistically significant. A difference in, or change in expression may be deemed significant if there is at least a 10% difference or increase or decrease for example. The test may be made more selective by making the change at least 15%, 20%, 25%, 30%, 35%, 40% or 50%, for example, in order to be considered statistically significant.
  • the level of KLF2 expression is determined with reference to a control sample.
  • This control sample is preferably taken from normal tissue in the subject, or from a normal tissue from a healthy subject.
  • control sample is taken from the same tissue as that under test at an earlier time point.
  • This is particularly relevant for assessing the effect of treatment, for example in order to ensure that treatment has been effective to modulate an immune response and/or treat or prevent an inflammatory condition.
  • suitability of an individual for treatment with a compound of the invention, or the effect of treatment of an individual may be monitored by determining the levels of KLF2 expression at appropriate time points.
  • the skilled person can identify appropriate time points before, during and after treatment through exercise of their ordinary skill.
  • Suitable additional controls may also be included to ensure that the methods are working properly, such as measuring expression of a suitable reference gene in both test and control samples .
  • the compound used in the method of assessing the suitability or effect of treatment may be in the form of a medicament or pharmaceutical composition of the invention.
  • Such methods provide the clear advantage that the most appropriate medicament, pharmaceutical composition or treatment for the individual may be selected from the full range of options available.
  • the methods of the invention provide the advantage that the effect of the medicament, pharmaceutical composition or treatment on the individual may be monitored, and if necessary changes made, for example in dosage, route of administration, treatment regimen etc.
  • a method of identifying genes whose expression is amenable to modulation by a compound according to the present invention comprises comparing the nucleotide sequence of a nucleic acid molecule of interest to the nucleotide sequence of any one of SEQ ID NOs. 1-5, wherein an identity of at least 90% between said any one of SEQ ID NOs.1-5 and a corresponding portion of the nucleotide sequence of the nucleic acid molecule of interest indicates that the nucleic acid molecule is operably linked to, or represents at least a portion of a gene whose expression is amenable to modulation by a compound according to the present invention.
  • operably linked refers to a functional linkage between a "regulatory" sequence and a nucleic acid molecule of interest, such that the
  • regulatory sequence is able to initiate transcription of the nucleic acid molecule.
  • the regulatory sequence may comprise any type of sequence known to influence gene expression, such as promoters and enhancers for example.
  • the regulatory sequence is preferably at least a portion of a promoter .
  • Methods for determining sequence identity are discussed above in more detail.
  • a method applicable to the present invention may be an in silico method, such as one that can be determined by bioinformatics homology/identity searches, for example by BLAST searches. Software for performing such homology/identity searches is widely available, for example via the internet .
  • the level of sequence identity may be 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.
  • the present invention also relates to the use of a nucleic acid molecule comprising a nucleotide sequence set forth in any one of SEQ ID NOs. 1-5 as a capture agent for identifying a molecule that binds to the nucleic acid molecule.
  • the molecule that binds may be any molecule with affinity for nucleic acid molecules, especially DNA, RNA, protein, and nucleic acid binding proteins . In this way further molecules with binding affinity for nucleic acid molecules with the sequence of any one of SEQ ID NOs. 1-5 may be identified.
  • the compounds, methods and uses of the invention may find application in an in vivo, ex vivo or in vitro context. It will be appreciated that the teaching of the invention applies to whole organisms and individual cells of said organisms either in situ or when removed ex vivo and maintained in culture for a period of time. Cultured cells may be returned to the organism after having been removed. Alternatively, the teaching of the present invention may be applied to cell lines grown in culture. Such cultured cell lines may be of any sort known to one skilled in the art, for example primary cell cultures or stable cell lines, optionally comprising further modifications .
  • Figure 1 shows the results of micro array analysis of C2C12 cells stimulated by NMP; all hybridization data was pre- processed and normalised.
  • N values are the log 2-fold changes between untreated cells and cells treated with 5mM NMP.
  • B values are log of the odds evaluation of whether a particular gene is differentially expressed in treated and untreated cells.
  • KLF2 appears twice but with two distinct probe IDs i.e. this transcript is represented twice on the arrays with two distinct probe sequences .
  • Figure 2 shows the results of Q-PCR analysis of KLF2 expression following stimulation of C2C12 cells by NMP or bone morphogenetic protein 2 (BMP2) .
  • KLF 2 expression levels have been normalised to expression levels of 18s rRNA.
  • FIG 3 shows KLF2 expression levels in cultured C2C12 cells over time, with and without treatment with 5mM NMP. KLF2 expression levels were assessed by Q-PCR and normalised to 18s rRNA expression levels. Maximal induction of KLF2 expression is already seen at the earliest time point shown, i.e. two hours .
  • Figure 4 shows the activation of the KLF2 promoter by NMP. 482 base pairs immediately 5 ' of the proposed transcriptional start site of the murine KLF2 promoter were PCR amplified and cloned upstream of the firefly luciferase reporter gene.
  • This construct was trasfected into C2C12 cells along with a Ren ⁇ lla luciferase construct for normalisation, and cells were stimulated for 24 hours with increasing concentrations of NMP. Firefly luciferase activity was determined by luminesence assay and normalised to Ren ⁇ lla luciferase activity. Dose dependent activation of the firefly luciferase reporter gene in response to NMP stimulation was observed.
  • Figure 5 shows the results of deletion analysis of the KLF2 promoter. Firefly luciferase reporter gene activity was determined by a luminesance assay and normalised to Renilla luciferase assay. Maximal expression of the reporter gene was observed using the ⁇ Apal construct, no reporter gene response was observed uising the ⁇ Sacl construct thereby indicating that a 111 base pair Apal/Sacl fragment is the location of the genetic element responsive to the compounds of the invention.
  • FIG. 6 shows Q-PCR analysis of KLF2 expression (normalised to 18s rRNA expression) cultured human umbilical vein endothelial cells (HUVECs) stimulated with NMP, TNF ⁇ or NMP in combination with TNF ⁇ . NMP opposes TNF ⁇ mediated inhibition of KLF2 expression.
  • KLF2 expression normalised to 18s rRNA expression
  • HAVECs human umbilical vein endothelial cells
  • FIG. 7 shows flow cytometric analysis of cultured human umbilical vein endothelial cells (HUVECs) treated with TNF ⁇ or TNF ⁇ in combination with NMP in comparison with untreated control cells.
  • Treatment of cells with NMP reduced the upregulation of VCAM-I expression in HUVECs in comparison to cells treated with TNF ⁇ alone.
  • FIG 8 shows sandwich ELISA analysis of IL-6 production by cultured human umbilical vein endothelial cells (HUVECs) with or without treatment with NMP and in the presence or absence of TNF ⁇ . A dose dependent inhibition of TNF ⁇ stimulated production of IL- 6 was observed.
  • HUVECs human umbilical vein endothelial cells
  • FIG. 9 shows sandwich ELISA analysis of MCP-I production by cultured human umbilical vein endothelial cells (HUVECs) with or without treatment with NMP and in the presence or absence of TNF ⁇ . A dose-dependent inhibition of TNF ⁇ stimulated production of MCP-I was observed.
  • HUVECs human umbilical vein endothelial cells
  • Figure 10 shows the results of Q-PCR analysis of KLF2 expression following stimulation of C2C12 cells by NMP, 1- vinyl-2-pyrollidone or 1-methyl-2-piperidone in comparison with untreated control cells.
  • KLF2 expression levels have been normalised to expression levels of 18s rRNA.
  • 1-vinyl- 2-pyrollidone and 1-methyl-2-piperidone each resulted in stronger stimulation of KLF2 than stimulation by NMP.
  • FIG 11 shows the results of Q-PCR analysis of KLF2 expression following stimulation of cultured human umbilical vein endothelial cells (HUVECs) by NMP, l-vinyl-2- pyrollidone or 1-methyl-2 -piperidone in comparison with untreated control cells.
  • KLF2 expression levels have been normalised to expression levels of 18s rRNA.
  • 1-vinyl-2- pyrollidone and 1-methyl-2-piperidone each resulted in stronger stimulation of KLF2 than stimulation by NMP.
  • Figure 12 shows an alignment between a highly conserved 63 base pair region within the Apal/Sacl fragment described above for both mouse and human sequences .
  • KLF2 may be modulated by compounds according to Figure 1 wherein X is methylene or a covalent bond; and R is hydrogen, methyl, ethyl, vinyl, n-propyl or isopropyl (i.e. compounds according to the invention) .
  • X is methylene or a covalent bond
  • R is hydrogen, methyl, ethyl, vinyl, n-propyl or isopropyl (i.e. compounds according to the invention) .
  • Treatment of cultured cells for example osteoblast cells or mesenchymal stem cells, with compounds according to the invention leads to enhanced KLF2 expression.
  • Time-course Q-PCR experiments show that KLF2 expression is enhanced as a result of treatment with the compounds of the invention within two hours of treatment (Figure 3) .
  • This timescale is not consistent with a requirement for new protein translation (i.e. the translation of a transcription factor acting upstream of KLF2) .
  • new protein translation i.e. the translation of a transcription factor acting upstream of KLF2
  • the compounds of the invention influence a signalling pathway which has a direct effect on KLF2 transcription.
  • the sequence of the KLF2 promoter region is provided in SEQ ID NO. 1. Deletion analysis of this promoter region defines a 111 base-pair Apal/Sacl fragment (shown in SEQ ID NO. 2) within the KLF2 promoter as the specific element which is responsive to the compounds of the invention ( Figure 5) .
  • TAAATTTA palindrome SEQ ID NO. 5
  • the TAAATTTA palindrome SEQ ID NO. 5
  • VCAM-I is an adhesion molecule which when expressed on the endothelial surface, adheres to and encourages the extravasation of inflammatory cells (such as monocytes) from the blood. VCAM-I is therefore a key regulator of the inflammatory state.
  • VCAM-I has also been shown to be repressed by ectopic KLF2 expression (4) and the present inventors have demonstrated that the compounds of the invention also regulate VCAM-I expression, presumably through its effects on KLF2 expression.
  • Flow cytometry shows that the compounds of the invention do indeed block VCAM-I expression induced by TNF ⁇ , significantly reducing the population of VCAM-I positive cells ( Figure 7) .
  • Inflammatory activation of cells also leads to the production of pro-inflammatory cytokines which are important in the inflammatory process .
  • endothelial cell activation and the production of pro-inflammatory cytokines are believed to be important in the atherosclerotic process .
  • the compounds of the invention antagonise the ability of TNF ⁇ to enhance the production of IL-6 and MCP-I.
  • the compounds of the invention appear to function as anti-inflammatory signals, blocking the production of an acute-phase inflammatory response.
  • the compounds of the invention would prevent the chemotaxis of monocytes from the circulation towards the endothelial cell layer and their subsequent extravasation. These processes are important in the development of an inflammatory response, in particular in the development of atherosclerotic lesions.
  • the compounds of the invention enhance expression of KLF2, thereby regulating expression of proposed KLF2 target genes such as VCAM-I. Given that absence of KLF2 leads to inappropriate immune responses, drugs capable of increasing KLF2 levels may also have the effect of enhancing immune responses .
  • the compounds of the invention therefore constitute a new class of adjuvants for boosting antigen- dependent immune responses in vaccines .
  • Example 2 Quantitative real time PCR (Q-PCR) C2C12 cells were plated in 6-well dishes, and incubated overnight with media alone, 5mM NMP or 100ng/nl bone morphogenetic protein 2 (BMP2) . RNA was prepared, reverse transcribed and analysed for KLF2 expression by Q-PCR. KLF2 expression was normalised to expression of the 18s rRNA gene, which is a suitable housekeeping control in C2C12 cells under these activation conditions. The results are shown in Figure 2.
  • Example 3 Quantitative real time PCR (Q-PCR) over 3 days C2C12 cells were stimulated with 5mM NMP and RNA prepared at various time points over a period of 3 days. KLF2 expression was assessed by Q-PCR and normalised to 18S rRNA expression. KLF2 expression was already maximally induced at first time point taken (2 hours) . The results are shown in Figure 3.
  • Example 5 Deletion analysis of the murine KLF2 promoter Deletion constructs were made starting from the original (Parental) murine KLF2 promoter using the Apal and Sad sites. These constructs were transfected into C2C12 cells along with a Renilla luciferase construct for normalisation, and cells were stimulated for 24 hours with 5mM NMP. Firefly luciferase activity was determined by a luminescence assay and normalised to Renilla luciferase activity. The results are shown in Figure 5.
  • HUVECs were cultured for 24 hours in media alone (Unstimulated) , 5mM NMP, lOng/ml recombinant human TNF ⁇ , or TNF ⁇ plus 5mM NMP.
  • RNA was prepared using Qiagen RNeasy, reverse transcribed and assessed for KLF2 mRNA expression by Q-PCR using SYBR Green detection chemistry. KLF2 expression is normalised to 18S rRNA expression. The results are shown in Figure 6.
  • HUVECs were cultured for 24 hours in media alone (Untreated) , l ⁇ ng/ml recombinant human TNF ⁇ , or TNF ⁇ plus 5mM NMP.
  • Cells were dissociated with PBS/0.5mM EDTA and stained for VCAM-I expression using a FITC-labelled anti- human VCAM-I monoclonal antibody. Staining was analysed on a Beckman-Coulter FC500 Flow Cytometer and analysed with CXP software. The bars represent regions set against the untreated control to show the proportion of VCAM-I-positive cells under different experimental conditions. The results are shown in Figure 7.
  • HUVECs were cultured for 24 hours in media alone, or with lng/ml recombinant human TNF ⁇ , along with increasing concentration of NMP.
  • IL-6 production was measured by sandwich ELISA using capture and detection antibodies from R and D Systems, and quantified by comparison to a serially- diluted recombinant IL-6 standard. The results are shown in Figure 8.
  • HUVECs were cultured for 24 hours in media alone, or with 1 or 10ng/ml recombinant human TNF ⁇ , along with increasing concentration of NMP.
  • MCP-I production was measured by sandwich ELISA using capture and detection antibodies from R and D Systems and quantified by comparison to a serially- diluted recombinant MCP-I standard. The results are shown in Figure 9.
  • Example 10 Quantitative real time PCR (Q-PCR) C2C12 cells were cultured for 24 hours with 5mM NMP, 5mM 1- vinyl-2-pyrrolidone, or 5mM 1-methyl-2-pieridone .
  • RNA was prepared using Qiagen RNeasy, reverse transcribed and assessed for KLF2 mRNA expression by Q-PCR using SYBR Green detection chemistry. KLF2 expression was normalised to 18S rRNA expression. The results are shown in Figure 10.
  • HUVECs were cultured for 24 hours with 5mM NMP, 5mM 1-vinyl- 2-pyrollidone, or 5mM 1-methyl-2-pieridone .
  • RNA was prepared using Qiagen RNeasy, reverse transcribed and assessed for human KLF2 mRNA expression by Q-PCR using SYBR Green detection chemistry. KLF2 expression is normalised to 18S rRNA expression. The results are shown in Figure 11
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl, for use as a medicament.
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, or acetyl, isopropyl, in the manufacture of a medicament for use in the modulation of an immune response and/or in the treatment or prevention of an inflammatory condition.
  • inflammatory condition is selected from acute inflammation, chronic inflammation, septic shock, arteriosclerosis, atherosclerosis, arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis or ankylosing spondylitis .
  • a method of modulating an immune response and/or of treating or preventing an inflammatory condition comprising administering to a subject in need thereof a therapeutically effective quantity of a compound of the formula :
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl isopropyl, or acetyl, whereby said method modulates said immune response or treats or prevents said inflammatory condition.
  • inflammatory condition is selected from acute inflammation, chronic inflammation, septic shock, arteriosclerosis, atherosclerosis, arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis or ankylosing spondylitis .
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl .
  • composition according to claim 26 further comprising at least one additional pharmaceutical compound.
  • composition according to claim 27 wherein the at least one addition pharmaceutical compound is selected from a vaccine, an anti-inflammatory drug and an anti-atherosclerotic drug.
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl and an additional pharmaceutical compound for simultaneous, separate or sequential use in the modulation of an immune response and/or the treatment or prevention of an inflammatory condition.
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl .
  • a method of manufacturing a coating for a medical device comprising combining at least one compound according to the formula:
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl or acetyl, with a polymer to form a coating.
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, or acetyl isopropyl .
  • kits comprising, a) a composition comprising at least one compound of the formula,
  • X is a covalent bond, methylene, or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl or isopropyl, or acetyl, and b) a medical device, wherein the composition of (a) may be used for coating the medical device of (b) .
  • kits comprising, a) a composition comprising at least one compound of the formula,
  • X is methylene or a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl, and
  • composition of a) may be combined with the composition of b) to form a coating composition for a medical device.
  • a method of increasing the expression of KLF2 in one or more cells comprising treating the one or more cells with a compound of the formula:
  • X is a covalent bond, methylene, or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl or acetyl .
  • X is methylene or a covalent bond, methylene, or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n- propyl, isopropyl, or acetyl the method comprising,
  • SEQ ID NOs. 1-5 wherein a level of sequence identity of at least 90% is indicative of the suitability of the individual to treatment with a compound as defined above.
  • X is a covalent bond, methylene, or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl or acetyl, wherein the method comprises comparing the nucleotide sequence of a nucleic acid molecule of interest to the sequence of any one of SEQ ID NOs. 1-5, wherein an identity of at least 90% between said any one of SEQ ID NOs.1-5 and a corresponding portion of the nucleotide sequence of the nucleic acid molecule of interest indicates the nucleic acid molecule is operably linked to or represents at least a portion of a gene whose expression is amenable to modulation by a compound according to formula I.
  • nucleic acid molecule comprising the nucleotide sequence set forth in any one of SEQ ID NOs . 1-5 as a capture agent for identifying a molecule that binds to the nucleic acid molecule.
  • the present invention relates to compounds of the formula:
  • X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl .

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pain & Pain Management (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention porte sur des composés de la formule (I) : dans laquelle X est une liaison covalente, méthylène ou éthylène; et R représente hydrogène, méthyle, éthyle, vinyle, n-propyle, isopropyle, ou acétyle pour moduler le facteur de transcription de type Kruppel 2 (KLF2). Ainsi, l'invention porte sur l'utilisation de ces composés pour la modulation de réponses immunitaires ainsi que pour le traitement de conditions inflammatoires.
PCT/GB2008/001460 2007-04-30 2008-04-25 Compositions utiles dans la modulation de réponses immunitaires et le traitement ou la prévention de réponses inflammatoires et procédés apparentés WO2008132458A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SB70812007 2007-04-30
SB0708120.1 2007-04-30

Publications (2)

Publication Number Publication Date
WO2008132458A1 true WO2008132458A1 (fr) 2008-11-06
WO2008132458A8 WO2008132458A8 (fr) 2009-07-16

Family

ID=39925236

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/001460 WO2008132458A1 (fr) 2007-04-30 2008-04-25 Compositions utiles dans la modulation de réponses immunitaires et le traitement ou la prévention de réponses inflammatoires et procédés apparentés

Country Status (1)

Country Link
WO (1) WO2008132458A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009016333A1 (fr) * 2007-07-30 2009-02-05 Inion Limited Composés ostéogéniques
JP2013032332A (ja) * 2011-07-01 2013-02-14 Lintec Corp 免疫賦活剤
EP2585060A1 (fr) * 2010-06-21 2013-05-01 Peter MacCallum Cancer Institute Stimulation de réponse immunitaire
US8987162B2 (en) 2010-08-13 2015-03-24 Ut-Battelle, Llc Hydrothermally stable, low-temperature NOx reduction NH3-SCR catalyst
WO2023150374A1 (fr) * 2022-02-07 2023-08-10 Riparian Pharmaceuticals, Inc. Inducteurs de klf2 et leurs procédés d'utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003047646A1 (fr) * 2001-12-04 2003-06-12 Inion Ltd Composition polymere resorbable, implant et procede de fabrication d'implant
WO2006069000A2 (fr) * 2004-12-21 2006-06-29 The Brigham And Women's Hospital, Inc. Klf2 utilise comme mediateur de l'activite des statines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003047646A1 (fr) * 2001-12-04 2003-06-12 Inion Ltd Composition polymere resorbable, implant et procede de fabrication d'implant
WO2006069000A2 (fr) * 2004-12-21 2006-06-29 The Brigham And Women's Hospital, Inc. Klf2 utilise comme mediateur de l'activite des statines

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHAPMAN J M JR ET AL: "HYPOLIPIDEMIC ACTIVITY OF PHTHALIMIDE DERIVATIVES 5. REDUCED AND HYDROLYTIC PRODUCTS OF SIMPLE CYCLIC IMIDES", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 73, no. 10, 1984, pages 1482 - 1484, XP009103639, ISSN: 0022-3549 *
LI C-D ET AL: "INDUCTION OF DIFFERENTIATION OF LEUKEMIA CELLS IN-VITRO BY N SUBSTITUTED AMIDES LACTAMS AND 2 PYRIDONES", JOURNAL OF MEDICINAL CHEMISTRY, vol. 24, no. 9, 1981, pages 1092 - 1094, XP002489468, ISSN: 0022-2623 *
PARMAR KUSH M ET AL: "Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2", JOURNAL OF CLINICAL INVESTIGATION, vol. 116, no. 1, January 2006 (2006-01-01), pages 49 - 58, XP002489473, ISSN: 0021-9738 *
REDDY P AMRUTA ET AL: "Synthesis and anticonvulsant activities of 3,3-dialkyl- and 3-alkyl-3-benzyl-2-piperidinones (delta-valerolactams) and hexahydro-2H-azepin-2-ones (epsilon-caprolactams)", JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 1, 1997, pages 44 - 49, XP002489466, ISSN: 0022-2623 *
SASAKI H ET AL: "ENHANCING EFFECT OF PYRROLIDONE DERIVATIVES ON TRANSDERMAL PENETRATION OF 5-FLUOROURACIL, TRIAMCINOLONE ACETONIDE, INDOMETHACIN, AND FLURBIPROFEN", JOURNAL OF PHARMACEUTICAL SCIENCE, US, vol. 80, no. 6, 1 June 1991 (1991-06-01), pages 533 - 538, XP009020814, ISSN: 0022-3549 *
SASAKI H ET AL: "Synthesis and anticonvulsant activity of 1-acyl-2-pyrrolidinone derivatives", JOURNAL OF MEDICINAL CHEMISTRY, USAMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 34, no. 2, 1 January 1991 (1991-01-01), pages 628 - 633, XP002082623, ISSN: 0022-2623 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009016333A1 (fr) * 2007-07-30 2009-02-05 Inion Limited Composés ostéogéniques
EP2585060A1 (fr) * 2010-06-21 2013-05-01 Peter MacCallum Cancer Institute Stimulation de réponse immunitaire
EP2585060A4 (fr) * 2010-06-21 2013-12-04 Peter Maccallum Cancer Inst Stimulation de réponse immunitaire
US9724329B2 (en) 2010-06-21 2017-08-08 Peter Maccallum Cancer Institute Stimulating immune response
US8987162B2 (en) 2010-08-13 2015-03-24 Ut-Battelle, Llc Hydrothermally stable, low-temperature NOx reduction NH3-SCR catalyst
JP2013032332A (ja) * 2011-07-01 2013-02-14 Lintec Corp 免疫賦活剤
US9475039B2 (en) 2012-02-24 2016-10-25 Ut-Battelle, Llc Hydrothermally stable, low-temperature NOx reduction NH3-SCR catalyst
US9694352B2 (en) 2012-02-24 2017-07-04 Ut-Battelle, Llc Method for treating engine exhaust by use of hydrothermally stable, low-temperature NOx reduction NH3-SCR catalysts
WO2023150374A1 (fr) * 2022-02-07 2023-08-10 Riparian Pharmaceuticals, Inc. Inducteurs de klf2 et leurs procédés d'utilisation

Also Published As

Publication number Publication date
WO2008132458A8 (fr) 2009-07-16

Similar Documents

Publication Publication Date Title
Huangfu et al. The IL-17 family in diseases: from bench to bedside
de Morales et al. Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies
Spalinger et al. PTPN2 regulates interactions between macrophages and intestinal epithelial cells to promote intestinal barrier function
Spronk et al. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation
Bai et al. AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis
Zhu et al. CXCL8 chemokine in ulcerative colitis
JP6212107B2 (ja) 脱毛障害を処置するための方法
US11034751B1 (en) Methods and compositions for treating cancer using serotonin receptor inhibitors
US20230013402A1 (en) Regenerating functions and phenotypes of connective tissue through npas2 suppression
WO2023051822A1 (fr) Oligonucléotide de ciblage pour le traitement de maladies associées à pcsk9
US20170137812A1 (en) Compositions and methods for modulating myeloid derived suppressor cells
US20230035892A1 (en) Methods and compositions for treating cancer
WO2008132458A1 (fr) Compositions utiles dans la modulation de réponses immunitaires et le traitement ou la prévention de réponses inflammatoires et procédés apparentés
US20180113139A1 (en) Methods and compositions for diagnosing and treating inflammatory bowel disorders
CN111956658B (zh) miRNA 148簇作为诊断和/或治疗认知障碍相关疾病标志物的应用
US20230130621A1 (en) Application of agent in preparation of medicine for treating/inhibiting psoriasis
Burel et al. Unique O-methoxyethyl ribose-DNA chimeric oligonucleotide induces an atypical melanoma differentiation-associated gene 5-dependent induction of type I interferon response
Ohshima et al. Fibroblast VEGF‐receptor 1 expression as molecular target in periodontitis
CN114887046B (zh) Spink4在治疗炎症性肠病中的应用
EP3380615B1 (fr) Oligonucléotides antisens il-34 et leurs procédés d'utilisation
US11802139B2 (en) Pharmaceutical composition and the use thereof in the treatment of autoimmune diseases
KR20070089980A (ko) 염증성 장 질환의 치료를 위한 치료용 안티센스올리고뉴클레오티드 조성물
US20230002770A1 (en) Il-34 antisense agents and methods of using same
US11771703B2 (en) Targeted epigenetic therapy against distal regulatory element of TGFβ2 expression
Wang et al. Suppressive effect of β, β-dimethylacryloyl alkannin on activated dendritic cells in psoriasis by the TLR7/8 pathway

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: 08737106

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

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

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO R.112(1) EPC

122 Ep: pct application non-entry in european phase

Ref document number: 08737106

Country of ref document: EP

Kind code of ref document: A1