GB2448871A - Modulation of inflammatory and immune responses in the treatment of inflammation using substituted heterocyclic compounds - Google Patents
Modulation of inflammatory and immune responses in the treatment of inflammation using substituted heterocyclic compounds Download PDFInfo
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- GB2448871A GB2448871A GB0708120A GB0708120A GB2448871A GB 2448871 A GB2448871 A GB 2448871A GB 0708120 A GB0708120 A GB 0708120A GB 0708120 A GB0708120 A GB 0708120A GB 2448871 A GB2448871 A GB 2448871A
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
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- 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]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
Landscapes
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- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compounds of the formula (I) below: <EMI ID=1.1 HE=38 WI=35 LX=881 LY=779 TI=CF> <PC>wherein X is a covalent bond, methylene or ethylene, R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropy; or acetyl may be used to treat inflammatory diseases such as arteriosclerosis, atherosclerosis, arthritis, psoriasis and ankylosing spondylitis. The compounds have been found to be active in modulating the levels of KLF2 in the body. Also disclosed are medical devices comprising such compounds, for example stents, cathaters and guidewires. Further disclosed is a method for assessing the response in a patient to a compound of the formula above which involves assessment of KLF2 expression levels in a patient both before and after treatment with the above compound and comparing the two results. Also disclosed is a method of identifying genes whose expression is amenable to modulation by the above compounds.
Description
COMPOSITIONS USEFUL IN THE MODULATION OF IMMUNE RESPONSES
AND THE TREATMENT OR PREVENTION OF INFLAMMATORY RESPONSES
AND RELATED METHODS
Field of Invention
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 spondvlitis.
Background of the Invention
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.
Kruppel-like transcription factor 2 (KLF2, according to the Hugo Gene Nomenclature Committee (HGNC), also known as Lung Kruppel-Like Factor (LKLF), was originally identified as an immunomodulatory transcription factor based on a hyper-reactive T-cell phenotype observed in RAG2-reconstituted KLF2 knockout mice (1). More recent studies have extended this phenotype (2) to show that KLF2 functions to promote T-cell egress from the thymus during immune challenge. This takes place in part by the ability of KLF2 to activate expression of a cell surface receptor (S1P1) which4is required for thymocyte exit from, as well as recirculation back to, the thymus. This trafficking of T-cells is vital to the maintenance of an appropriate immune response to antigen challenge. Thus KLF2 plays a role in the development of antigen-dependent immune responses.
Subsequently, KLF2 has also attracted interest as a more general modulator of inflammation and localised vascular thrombosis. In particular, 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. Without wishing to be bound by theory, the current opinion in the field is that KLF2 is a master regulator of atheroprotective transcriptional programs (3).
Furthermore, 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.
It would be useful if there were further active ingredients useful in the modulation of an immune response and/or the treatment or prevention of an inflammatory condition, including inflammatory responses of the vascular endothelium associated with atherosclerosis.
It is an object of the invention to provide medicaments useful in the treatment of immune conditions or in1ammatory conditions or to at least provide the public and/or medical community with a useful alternative.
Summary of the Invent ion
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.
Accordingly, in a first aspect, the present invention provides use of a compound of the formula: [Formula I] wherein 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.
In a preferred embodiment, 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).
In a preferred embodiment, 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.
In a preferred embodiment, 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 l-methyl-2-piperidone.
In a preferred embodiment, the compound for use in the manufacture of a medjcament as described above has X as ethylene and R as methyl. This compound is referred to as N-rnethylcaprolactam.
In a preferred embodiment, 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.
By "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 levated 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. In preferred embodiments, 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 medicanients 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. Those excipients used in the art are generally well known and may include fillers, lubricants, colours, flavours, wetting agnts, solvents, buffering agents, preservatives and the like.
In some embodiments, the medicaments may contain one or more additional pharmaceutical compounds. In preferred embodiments 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.
In preferred embodiments, the at least one additional anti-inflammatory drug comprises a non-steroidal anti-inflammatory drug (NSAID). Preferably the medicaments comprise at least one compound according to the present invention together with ibuprof en and/or aspirin.
In a further aspect, the present invention provides a compound of the formula [Formula II for use as a medicament, wherein X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl.
In a preferred embodiment, the compound of the present invention has X as a covalent bond and R as methyl1 (N-methyl-pyrroljdorie, NMP).
In a preferred embodiment, the compound of the present invention has X as a covalent bond and R as vinyl (1-vinyl- 2-pyrrolidone).
In a preferred embodiment, the compound of the present invention has X as methylene and R as methyl (1-methyl-2-piperidone).
In a preferred embodiment, 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.
In a further aspect the present invention provides a method of treatment for modulating an immune response, and/or of treating or preventing an inflammatory condition. For example, 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. In preferred embodiments, medicaments of the invention may additionally comprise one or more vaccines.
This discussion of the first aspect of the invention applies mutatis mutandjs to this aspect of the invention. As discussed in further detail herein, by "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.
As mentioned above, preferred compounds for use in the methods of treatment of the invention are such that X is a covalent bond and R as methyl (N-.methyl-pyrrolidone, NMP); X is a covalent bond and R as vinyl (1-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. In this way 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. In preferred embodiments, the inflammatory condition to be treated by the method according to the present invçntion is selected from the group comprising acute inflammation, chronic inflammation, septic shock, arteriosclerosis, atherosclerosis, arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis or ankylosing spondylitis.
In a further aspect, 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 -10 -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.
In particularly preferred embodiments the pharmaceutical composition includes at least one pharmaceutically acceptable excipient.
The 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.
The 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. For example, one medicament according to the invention may simply comprise a s9lution of the active agents in a suitable solvent, for example dime thyl sulphoxide.
The compositions and medicaments according to the invention may be manufactured using any suitable method. For example, the compositions may be dry milled and mixed prior to tableting and the composition may therefore necessarily contain other pharmaceutically acceptable excipierits 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, -11 -hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and a polyvinyl pyrrolidone (PVP).
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. Some examples of excipients for use in the
compositions and rnedicaments of the present invention are microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, and titanium dioxide.
For oral administration compositions or medicarnents 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 b 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. When the dosage unit is a capsule it may additionally contain a liquid carrier such as an oil or buffered aqueous solution.
-12 -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, liposornes.
Pharmaceutical formulations 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, trichioroethano]., 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) Medjcaments and compositions of the invention suitable for rectal or vaginal administration may be presented as a suppository, which may include one or more suitable -13 -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.
Disclosed herein are medicaments, uses, compositions and methods for modulating an immune response and/or treating inflammatory conditions in a subject, preferably a subject in need of such treatment. The subject is most preferably human. As used herein, 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. However, the medicament compositions may be simply taken as a prophylactic.
As mentioned above, 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.
Thus, for example, the present method of "treating" an inflammatory condition, as the term is used herein, -14 -encompasses both prevention of the disorder and treatment of the disorder in a clinically symptomatic individual.
The term "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.
In preferred embodiments 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 3110w for additive or potentially synergistic effects between the compounds of the invention and the further pharmaceutical compounds. Furthermore, 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.
In a particularly preferred embodiment of the invention, 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- -15 -inflammatory drug and/or anti-atherosclerotic drug. Any suitable ani-inflammatory and/or anti-atherosclerotic may be used.
In preferred embodiments, the at least one additional anti-inflammatory drug comprises a non-steroidal anti-inflammatory drug (NSAID). Preferably the medicaments comprise at least one compound according to the present invention together with ibuprof en and/or aspirin.
Preferably the ibuprofen and/or aspirin is present in an amount of less than 250 mg, more preferably less than 100 ing daily. Preferably 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. In this way 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.
In a further aspect, 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 -16 -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.
By "therapeutically effective amount" is meant an amount of the compound sufficient to give rise to the desired therapeutic effect. For example, the therapeutically effective amount is an amount sufficient to modulate an immune response or to treat or prevent an inflammatory condition.
In a yet further aspect, the present invention relates to a medical device comprising at least one compound according to the present invention. In some embodiments the medical device may be manufactured separately and then have the compounds of the invention applied to one or more surfaces.
Alternatively compounds of the invention may be, f9r 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 -17 -
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. In specific embodiments, 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. As for other aspects of the invention, the subject is most preferably a human subject.
In one preferred embodiment, 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.
In further preferred embodiments the device may be biodegradable, for example a biodegradable stent. In addition, or alternatively, the coating comprising,the compound of the invention may be biodegradable.
In one embodiment, the compound of the invention is adsorbed onto 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.
In one embodiment, a co-polymer blend is utilised. Examples of suitable polymers into which the compounds of the -18 -invention may be (rion-covalently) incorporated include, but are not limited to, poly(hexano-6-lactone), poly(ethylerie-co-vinyl acetate) (EVA), poly(ethylene oxide) (PEO), polyvinylpyrollidone, poly(tetrafluoroe-thylene) (PTFE), s poly(dimethylsjlo-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 (I-i]JPE), polysulfones, polyviriylchloride (PvC), poly(2-hydroxyethylmethacrylate (PHEMA) and polylactide and blends thereof such as poly(hexano-6-lactone)/polyactide blends and EVA/PEO blends. 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.
-19 -In one specific embodiment, 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. Examples of 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.
In a further aspect, the invention relates to a medical device when made according to an appropriate method of the invention.
In a further aspect, 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 -20 -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.
By "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 inlength. In preferred embodiments according to (c) above the level of sequence identity may be 911, 92%, 93%, 94%, 951, 96%, 97%, 98%, 99% or 100%.
Methods for determining sequence identity are routine in the art and include use of the BLAST software and EMBOSS software (The European Molecular Biology Open Software Suite (2000), Rice,P. Longden, I. and Bleasby, A. Trends, in Genetics 16, (6) pp276-277) . The term "identity" as used herein 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 -21 -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.
It will also be apparent to the skilled person that the method described above could be considered as a way of assessing whether compounds of the invention are suitable for treating a given individual.
In a related aspect, 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 pbtained 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.
In preferred embodiments 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.
-22 -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.
By "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.
In appropriate embodiments, 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.
Alternatively, the 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, -23 -f or example in order to ensure that treatment has been effective to modulate an immune response and/or treat or prevent an inflammatory condition. Thus, 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 medicarnent or pharmaceutical composition of the invention.
It will be apparent to one of skill in the art that the methods of assessing suitability of an individual to treatment or assessing the effect of treatment on an individual with a compound according to the invention may be used in order to provide a personalised medicine approach to treatment of the individual. According to these methods it is possible to determine if an individual is likely to respond positively to treatment with the compounds of the invention and furthermore, if such treatment is undertaken, to assess the effect of said treatment.
Such methods provide the clear advantage that the most appropriate rnedicament, pharmaceutical composition or -24 -treatment for the individual may be selected from the full range of options available. In addition, the methods of the invention provide the advantage that the effect of the medicatnent, pharmaceutical cornpo1ition or treatment on the individual may be monitored, and if necessary changes made, for example in dosage, route of administration, treatment regimen etc. In a further aspect of the invention, there is provided a method of identifying genes whose expression is amenable to modulation by a compound according to the present invention, wherein the method 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.l-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.
The term "operably linked" as used herein refers to a functional linkage between a regulatory" sequence and a nucleic acid molecule of interest, such that the "regulatory'1 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.
-25 -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 bioinforinatics homology/identity searches, for example by BLAST searches. Software for performing such homology/identity searches is widely available, for example via the internet.
In preferred method of identifying genes as above, 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.
It is envisaged that the compounds, methods and uses of the invention may find application in an in vivo, ex vivc 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.
-26 -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.
Brief description of the Figures
The invention will now be described by way of exemplification only and with reference to the accompanying figures, in which: Figure 1 shows the results of micro array analysis of C2C12 cells stimulated by NMP; all hybridization data was pre-processed arid 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.
Figure 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 rR.NA expression levels. Maximal induction of KLF2 expression is already seen at the earliest time point shown, i.e. two hours.
-27 -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 lucif erase reporter gene. This construct was trasfected into C2C12 cells along with a Renilla 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 Renilla 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 iApa1 construct, no reporter gene response was observed uising the Sac1 construct thereby indicating that a 111 base pair Apal/Saci fragment is the location of the genetic element responsive to the compounds of the invention.
Figure 6 shows Q-PCR analysis of KLF2 expression (normalised to l8s rRNA expression) cultured human umbilical vein endothelial cells (iltJVECs) stimulated with NMP, TNFc or NMP in combination with TNFc. NMP opposes TNFc mediated inhibition of KLF2 expression.
Figure 7 shows flow cytometric analysis of cultured human umbilical vein endotheijal cells (HIJVECs) treated with TNFc -28 -or TNFc in combination with NMP in comparison with untreated control cells. Treatment of cells with NMP reduced the upregulation of VCAN-l expression in HtJVECs in comparison to cells treated with TNFa alone.
Figure 8 shows sandwich ELISA analysis of IL-6 production by cultured human umbilical vein endothelial cells (HUVECs) with or without treatment with NM? and in the presence or absence of TNFcx. A dose dependent inhibition of TNFa stimulated production of IL-6 was observed.
Figure 9 shows sandwich ELISA analysis of MCP-1 production by cultured human umbilical vein endothelial cells (HUVECs) with or without treatment with NM? and in the presence or absence of TNFcx. A dose-dependent inhibition of TNFcx stimulated production of MCP-l was observed.
Figure 10 shows the results of Q-PCR analysis of KLF2 expression following stimulation of C2C12 cells by1N1P, 1-vinyl-2-pyrollidone or l-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 NM?.
Figure 11 shows the results of Q-PCR analysis of KLF2 expression following stimulation of cultured human umbilical vein endothelial cells (HUVECs) by NM?, l-vinyl-2-pyrollidone or l-methyl-2-piperidone in comparison with untreated control cells. KLF2 expression levels have been normalised to expression levels of lBs rRNA. 1-vinyl-2- -29 -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/Saci fragment described above for both mouse and human sequences.
The invention will now be described by way of reference to the examples. The examples discussed in the description are intended in no way to limit the scope of the invention as defined in the accompanying claims.
Description of the Invention
It has surprisingly been found that the expression of 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). Treatment of cultured cells, for example osteoblast cells or mesenchymal stem c1ls, with compounds according to the invention leads to enhanced KLF2 expression. Studies of endothelial cells in culture have also shown that treatment with compounds of the invention prevents the expression of the key cell surface adhesion molecule VCAM-J. and the acute -phase inflammatory cytokine, IL-6 and a chemokine (MCP-l) which promotes monocyte recruitment to the endotheijum. These observations indicate that compounds according to the invention may be used to modulate KLF2 expression, thereby providing an opportunity to modulate stem cell behaviour, immune responses and inflammatory responses.
-30 -Stem cell behaviour may be modulated in an appropriate manner for therapeutic applications such as the therapeutic use of cardiomyocytes for treatment of damage following myocardial infarction. Immune responses may be modulated for example such that antigen dependent responses are enhanced. Inflammatory responses may for example be modulated at the level of endothelial cells.
Micro-array analysis was performed on the murine cell line C2C12. This analysis revealed that such treatment leads to increased expression of KLF2 (Figure 1) . These results were confirmed by quantitative real-time PCR (Q-PCR) in independent experiments on cultured C2C12 cells (Figure 2 and Figure 10) and primary cultures of human umbilical vein endothelial cells (HUVECs) (Figure 6 and Figure 11).
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). Without wishing to be bound by theory it is believed that the compounds of the invention influence a signalling pathway which has a direct effect on KLF2 transcription.
This surprising finding has been confirmed and extended further by analysing the effect of compounds of the invention on the proximal region of the mouse KLF2 promoter region. Reporter constructs comprising the mouse KLF2 promoter region operably linked to the firefly luciferase reporter gene were employed. These experiments show that -31 -compounds of the invention can activate transcription from the KLF2 promoter in a dose-dependent manner (Figure 4).
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/Saci 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) Within this fragment there are several putative transcription factor binding sites. As such, and of particular interest is the 63 base pair sequence shown in SEQ ID NO. 3. There is very high homology between the mouse and human (SEQ ID NO. 4) sequences in this region. See Figure 12 which shows an alignment of the human and mouse sequences illustrating identity between 62 of the 63 nucleotides at this highly conserved locus.
The T?AATTTA palindrome (SEQ ID NO. 5) which is present within the highly conserved 63 base pair region identified above, and identical between the human and mouse sequences, is a good match for the Mef 2 family of transcription factors. Without wishing to be bound by theory, it seems likely that the compounds of the invention act on KLF2 via a member of the Mef 2 transcription factor family.
Further studies on KLF2 expression were carried out in primary cultures of human umbilical vein endothelial cells (HUVECs) . These cells are the in vitro tool of choice for modelling the cell biology of the endothelium, including the vascular endothelium lining blood vessels. The surprising finding that the compounds of the invention enhanced the -32 -expression of KLF2 in C2C12 cells was thus extended to HUVECs. The compounds of the invention also enhance the expression of KLF2 in HUVECs (Figure 6 and Figure 11).
S It was also noted that whereas inflammatory abuse of HtJVECs with the cytokine TNFa decreases expression of KLF2, coincident treatment with compounds of the invention opposes this effect and maintains KLF2 expression at basal levels (Figure 6). Thus, these observations strongly suggest that compounds of the invention can oppose pro-inflammatory insults to cells.
The effect of the compounds of the invention on expression of the endothej.ia]. activation marker, VCAM-i, was analysed.
VCAM-l 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-1 is therefore a key regulator of the inflammatory state.
VCAM-1 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 VCAN-l expression, presumably through its effects on KLF2 expression. Flow cytometry shows that the compounds of the invention do indeed block VCAM-1 expression induced by TNFcx, significantly reducing the population of VCAM-1 positive cells (Figure 7) Inflammatory activation of cells, such as endothelial cells, also leads to the production of pro-inflammatory cytokines which are important in the inflammatory process. For -33 -example, endothelial cell activation and the production of pro-inflammatory cytokines are believed to be important in the atherosclerotic process. As demonstrated in Figures 8 and 9, the compounds of the invention antagonise the ability of TNFX to enhance the production of IL-6 and MCP-l.
This finding has two consequences. Firstly, by reducing IL- 6 production, the compounds of the invention appear to function as anti-inflammatory signals, blocking the production of an acute-phase inflammatory response.
Secondly, in opposing MCP-l production (for example in endothelial cells), 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 Qf KLF2, thereby regulating expression of proposed KLF2 target genes such as VCAN-1. 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.
Examples
Example 1 Microarray analysis of C2C12 cells 3x106 C2C12 cells were stimulated for 8 hours with 5mM NMP, then total RNA was prepared using the Qiagen RNeasy system.
-34 -RNA was labelled and hybridised to ABI 1700 Mouse Genome Survey arrays. All hybridisation data was pre-processed and normalised. The results are shown in Figure 1.
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 lOOng/ni 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 4 Luciferase Reporter gene assay 482 base-pairs immediately 5' of the proposed transcriptional start of the murine KLF2 promoter were PCR-amplified and cloned upstream of the firefly luciferase reporter gene. This construct was transfected into C2C12 cells along with a Renilla luciferase construct for normalisation, and cells were stimulated for 24 hours with increasing concentrations of NMP. Firefly luciferase -35 -activity was determined by a luminescence assay and normalised to Renilla luciferase activity. The results are shown in Figure 4.
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.
Example 6 Anti-inflammatory action in HUVECs (1) 1-IUVECs were cultured for 24 hours in media alone (Unstimulated), 5mM NMP, long/mi recombinant human,TNFc, or TNFa 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.
Example 7 Anti-inflammatory action in HUVECs (2) HTJVECs were cultured for 24 hours in media alone (Untreated), long/mi recombinant human TNFc, or TNFa plus 5mM NMP. Cells were dissociated with PBS/0.5mM EDTA and stained for VCAM-i expression using a FITC-labelied anti-human VCAM-1 monoclorial antibody. staining was analysed on a -36 -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-l-positive cells under different experimental conditions. The results are shown in Figure 7.
Example 8 Anti-inflammatory action in HtJVECs (3) HUVECs were cultured for 24 hours in media alone, or with ing/mi recombinant human TNFc, 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.
Example 9 Anti-inflammatory action in HUVECs (4) HUVECs were cultured for 24 hours in media alone, q,r with 1 or long/mi recombinant human TNFc, along with increasing concentration of N1"IP. MCP-1 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-l 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. R.NA was prepared using Qiagen RNeasy, reverse transcribed and assessed for KLF2 rnRNA expression by Q-PCR using SYBR Green -37 -detection chemistry. KLF2 expression was normalised to 18S rRNA expression. The results are shown in Figure 10.
Example 11 Quantitative real time PCR (Q-PCR) HUVECs were cultured for 24 hours with 5mM NMP, 5mM 1-vinyl- 2-pyrollidone, or 5mM l-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 lBS rRNA expression. The results are shown in Figure 11 Various aspects of the present invention have been exemplified in the preceding section of the specification.
The discussion of these examples is intended for exemplification purposes only and is not intended to restrict in any way the scope of the invention as claimed in the appended claims.
References All of these references are hereby incorporated into the
present disclosure in their entirety.
(1) Kuo CT et al., Science 1997; 278 (5339): 788-9 (2) Carison CM et al., Nature, 2006; 442 (7100): 299-302 (3) Parmar et al., J. Clin. Invest. 2006, 116, 49-58 (4) Dekker et al., Blood, 2006, 107, 4354-63 (5) Glover et al., PL0S Comput Biol. 2006 Nov 24;2(ll):e158
Claims (52)
1. A compound of the formula: wherein 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.
2. The compound of claim 1 wherein X is a covalent bond and R is methyl.
3. The compound of claim 3. wherein X is a covalent bond and R is vinyl.
4. The compound of claim 1 wherein X is methylene and R is methyl.
5. The compound of claim 1 wherein X is ethylene and R is methyl.
6. The compound of claim 1 wherein X is ethylene and R is acetyl.
7. Use of a compound of the formula: -39 - [Formula I] wherein X is a covalent bond, methylene or ethylene; and P. 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.
8. Use according to claim 6 wherein X is a covalent bond and P. is methyl.
9. Use according to claim 6 wherein X is a covalent bond and R is vinyl.
10. Use according to claim 6 wherein X is methylene and P. is methyl.
11. Use according to claim 6 wherein X is ethylene and R is methyl.
12. Use according to claim 6 wherein X is ethylene and R is acetyl.
13. Use according to any one of claims 6 to 12 wherein the inflammatory condition is selected from acute inflammation, chronic inflammation, septic shock, arteriosclerosis, atherosclerosis, arthritis, rheumatoid -40 -arthritis, psoriasis, psoriatic arthritis or ankylosing spondylitis.
14. Use according to any one of claims 6 to 13 wherein the medicament is for systemic administration.
15. Use according to any one of claims 6 to 13 wherein the medicament is for localised administration.
16. 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: [Formula I] wherein 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.
17. The method of claim 16 wherein X is a covalent bond and R is methyl.
18. The method of claim 16 wherein X is a covalent -41 -bond and R is vinyl.
19. The method of claim 16 wherein X is methylene and R is methyl.
20. The method of claim 16 wherein X is ethylene and R is methyl.
21. The method of claim 16 wherein X is ethylene and R is acetyl.
22. The method of any one of claims 16 to 21 wherein the compound is administered simultaneously, separately or sequentially with a vaccine.
23. The method of any one of claims 16 to 22 wherein the inflammatory condition is selected from acute inflammation, chronic inflammation, septic shock, arteriosclerosis, atherosclerosis, arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis or ankylosing spondylitis.
24. The method of any one of claims 16 to 23 wherein the compound is administered systemically.
25. The method of any one of claims 16 to 23 wherein the compound is administered locally
26. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to the formula: -42 - [Formula I] wherein X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl.
27. The pharmaceutical composition according to claim 26 further comprising at least one additional pharmaceutical compound.
28. The pharmaceutical 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.
29. A product containing a compound according to the formula [Formula I] wherein X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, -43 -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.
30. A coating composition for a medical device wherein the coating composition comprises a therapeutically effective amount of a compound according to the formula: [Formula I] wherein X is a covalent bond, rnethylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl.
31. A medical device comprising a therapeutically effective amount of a compound according to the formula: [Formula I] -44 -wherein X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl or isopropyl and wherein; a) the compound according to Formula I is comprised in the medical device itself, or b) the compound according to Formula I is comprised in a coating which has been applied to the medical device.
32. The pharmaceutical composition according to any one of claims 26 to 28, the product according to claim 29, the coating composition according to claim 30 or the medical device according to claim 32 wherein X is a covalent bond and R is methyl.
33. The pharmaceutical composition according to any one of claims 26 to 28, the product according to claim 29, the coating composition according to claim 30 or the medical device according to claim 31 wherein X ip a covalent bond and R is vinyl.
34. The pharmaceutical composition according to any one of claims 26 to 28, the product according to claim 29, the coating composition according to claim 30 or the medical device according to claim 31 wherein X is methylene and R is methyl.
35. The pharmaceutical composition according to any one of claims 26 to 28, the product according to claim 29, the coating composition according to claim 30 or the medical device according to claim 31 wherein X is ethylene and R is methyl -45 -
36. The pharmaceutical composition according to any one of claims 26 to 28, the product according to claim 29, the coating composition according to claim 30 or the medical device according to claim 31 wherein X ethylene and R is acetyl.
37. A method of manufacturing a coating for a medical device comprising combining at least one compound according to the formula: [Formula I] wherein 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.
38. A method of manufacturing a medical device comprising coating at least a portion of said medical device with a therapeutically effective amount of a coating comprising a compound according to the formula: -46 -[Formula I] wherein X is a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-.propyl, or acetyl isopropyl.
39. The method of claim 37 or claim 38 wherein X is a covalent bond and R is methyl.
40. The method of claim 37 or claim 38 wherein X is a covalent bond and R is vinyl.
41. The method of claim 37 or claim 38 wherein X is methylene and R is methyl.
42. The method of claim 37 or claim 38 wherein X is ethylene and R is methyl.
43. The method of claim 37 or claim 38 wherei,n X is ethylene and R is acetyl.
44. Use of a coating composition as defined in claim or 32 to 36 for coating a medical device.
45. A kit comprising, a) a composition comprising at least one compound of the formula, -47 [Formula I] wherein X is a covalent bond, methylene, or ethylene; and R is hydrogen, methyl, ethyl, vinyl, S 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)
46. A kit comprising, a) a composition comprising at least one compound of the formula, [Formula I] 1 wherein X is methylene or a covalent bond, methylene or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl, and b) a coating composition or composition that is suitable for use as a coating composition or coating composition pre-curser, wherein the composition of a) may be combined with the composition of b) to form a coating composition for a medical device.
-48 -
47. A method of increasing the expression of KLF2 in one or more cells, wherein the method comprises treating the one or more cells with a compound of the formula: [Formula I] wherein X is a covalent bond, methylene, or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl or acetyl.
48. A method of assessing the suitability of an individual for treatment with a compound of the formula: [Formula I] wherein 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, 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 -49 -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.
49. A method of assessing the effect of treatment of an individual with a compound of the formula: [Formula I) -50 -wherein X is a covalent bond, methylene, or ethylene; and R is hydrogen, methyl, ethyl, vinyl, n-propyl, isopropyl, or acetyl the method comprising, a) in a test sample taken from the individual before treatment of the individual with a compound as defined above determining the level of KLF2 expression, b) in a test sample taken from the individual after treatment of the individual with a compound as defined above 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 a positive effect of treatment of the individual with a compound as defined above.
50. The method according to claim 39, further comprising comparing the levels of KLF2 expression in further samples that have been taken from the subject at time points subsequent to time points a) and b).
51. A method of identifying genes whose expression is amenable to modulation by a compound according to the formula: -51 - [Formula I] wherein 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.
52. Use of a 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.
e14897, MBG, L.P
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0708120A GB2448871A (en) | 2007-04-30 | 2007-04-30 | Modulation of inflammatory and immune responses in the treatment of inflammation using substituted heterocyclic compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0708120A GB2448871A (en) | 2007-04-30 | 2007-04-30 | Modulation of inflammatory and immune responses in the treatment of inflammation using substituted heterocyclic compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB0708120D0 GB0708120D0 (en) | 2007-06-06 |
| GB2448871A true GB2448871A (en) | 2008-11-05 |
| GB2448871A9 GB2448871A9 (en) | 2008-11-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| GB0708120A Withdrawn GB2448871A (en) | 2007-04-30 | 2007-04-30 | Modulation of inflammatory and immune responses in the treatment of inflammation using substituted heterocyclic compounds |
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| Country | Link |
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| GB (1) | GB2448871A (en) |
Citations (5)
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|---|---|---|---|---|
| US5049580A (en) * | 1989-11-20 | 1991-09-17 | Total Leather Care, Inc. | Treatment of inflamed skin conditions including poison ivy and poison sumac, insect bites and acne |
| WO1996003164A1 (en) * | 1994-07-22 | 1996-02-08 | Advanced Cardiovascular Systems, Inc. | Hydrophilic coating material for intracorporeal use |
| US6231600B1 (en) * | 1995-02-22 | 2001-05-15 | Scimed Life Systems, Inc. | Stents with hybrid coating for medical devices |
| WO2004000271A1 (en) * | 2002-06-21 | 2003-12-31 | Dermatrends, Inc. | Use of bases for the manufacture of a medicament in the treatment of different forms of inflammatory dermatosis |
| WO2006122414A1 (en) * | 2005-05-17 | 2006-11-23 | Matregen Corp. | Depot for sustained and controlled delivery of methotrexate |
-
2007
- 2007-04-30 GB GB0708120A patent/GB2448871A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5049580A (en) * | 1989-11-20 | 1991-09-17 | Total Leather Care, Inc. | Treatment of inflamed skin conditions including poison ivy and poison sumac, insect bites and acne |
| WO1996003164A1 (en) * | 1994-07-22 | 1996-02-08 | Advanced Cardiovascular Systems, Inc. | Hydrophilic coating material for intracorporeal use |
| US6231600B1 (en) * | 1995-02-22 | 2001-05-15 | Scimed Life Systems, Inc. | Stents with hybrid coating for medical devices |
| WO2004000271A1 (en) * | 2002-06-21 | 2003-12-31 | Dermatrends, Inc. | Use of bases for the manufacture of a medicament in the treatment of different forms of inflammatory dermatosis |
| WO2006122414A1 (en) * | 2005-05-17 | 2006-11-23 | Matregen Corp. | Depot for sustained and controlled delivery of methotrexate |
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| "Action des amides et en perticulier du N,N-diethylacetamide dans la prevention du choc traumatique du Rat" * |
| "Synthesis and anti-convulsant activity of 1-acyl-2-pyrrolodinone derivatives" * |
| Gene, Vol.236, 1999, Schrick, J. J. et al., "Characterization of the lung...", pp.185-195 * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0708120D0 (en) | 2007-06-06 |
| GB2448871A9 (en) | 2008-11-26 |
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