GB2624633A - Compounds for use in the treatment of diseases and conditions associated with inflammation or autoimmunity - Google Patents
Compounds for use in the treatment of diseases and conditions associated with inflammation or autoimmunity Download PDFInfo
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- GB2624633A GB2624633A GB2217453.6A GB202217453A GB2624633A GB 2624633 A GB2624633 A GB 2624633A GB 202217453 A GB202217453 A GB 202217453A GB 2624633 A GB2624633 A GB 2624633A
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Classifications
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
4-(6-oxo-2-(trifluoromethyl)-3,6-dichromeno[7,8-d]imidazole-8-yl)benzonitrile, also known as CF3CN, for use in the treatment of diseases or conditions associated with inflammation or autoimmunity, is provided. CF3CN is preferably administered with one or more pharmaceutically acceptable excipients. The diseases or conditions associated with inflammation or autoimmunity are as herein defined. The neuroprotective effect of CF3CN on damage induced by LPS on culture of mesencephalic neurons is exemplified. CF3CN may be administered as a single or multiple daily doses wherein the dose comprises at least 0.001mg of CF3CN. CF3CN may be administered with one or more additional drug products.
Description
COMPOUNDS FOR USE IN THE TREATMENT OF DISEASES AND CONDITIONS
ASSOCIATED WITH INFLAMMATION OR AUTOIMMUNITY
FIELD OF THE INVENTION
[0001] The present invention relates to the compound 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d] imidazol-8-yObenzonitrile, also known as CF3CN, referred to herein as the compound of Formula I, for use in the treatment of diseases and conditions associated with inflammation or autoimmunity.
BACKGROUND TO THE INVENTION
[0002] The compound tropoflavin, also known as 7,8-dihydroxyflavone (7,8-DHF), is a naturally occurring flavone found in Godmania aescurifolio, Tridax procumbent and primula tree leaves. It is known to act as a potent and selective agonist of tropomyosin receptor kinase B (TrkB), which is the main signaling receptor of neurotrophin brain-derived neurotrophic factor (BDNF). [0003] Tropoflavin has been shown to have therapeutic efficacy in several animal models including depression, Alzheimer's disease, cognitive deficits in schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral ischemia, fragile X syndrome and Rett syndrome.
[0004] A derivative of tropoflavin, 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl) benzonitrile, also known as CF3CN, referred to herein as the compound of Formula I, has been shown to be useful in the treatment of diseases and conditions associated with inflammation or autoimmunity.
[0005] Activation of the 5-HT2A receptors has been shown in animal models to produce a potent anti-inflammatory effect in an animal model of inflammatory disorders.
[0006] Inflammatory diseases occur when ongoing inflammation in a patient's body does not subside and return to its normal healthy state. Many factors can increase a person's risk for developing inflammatory disorders such as smoking, genetics, diet, and pollutants.
[0007] Autoimmune diseases occur when the body's immune system turns itself on or overreacts causing chronic inflammation.
[0008] There are many hundred different diseases and conditions associated with inflammation or autoimmunity including: acne vulgaris; acute inflammation; Addison's disease; allergic reactions; allergies; Alzheimer's disease; ankylosing spondylitis; aplastic anemia; asthma; atherosclerosis; autoimmune vasculitis; cancer; celiac disease; chronic inflammatory demyelinafing polyneuropathy (CI DP); chronic obstructive pulmonary disease (COPD); colitis; diverticulitis; endometriosis; familial Mediterranean fever; fatty liver disease; glomerulonephritis; Grave's disease; Guillain-Barre syndrome; Hashimoto's thyroiditis; headaches, including chronic headaches and migraine; hemolytic anemia; hidradenifis suppurafiva; HIV and AIDS; hypersensitivity reactions; immune-mediated inflammatory disease (I MID); inflammatory bowel disease such as Crohn's disease and ulcerative colitis; inflammatory myopathies; interstitial cystitis; leukocyte defects; lichen planus; mast cell activation syndrome; mastocytosis; mental health conditions where inflammation and/or autoimmunity is a co-morbid or causative factor, including; depression, schizophrenia, and anxiety; multiple sclerosis; myasthenia gravis; obesity; otitis; pain, including acute and chronic pain; Parkinson's disease; pelvic Inflammatory disorder; peripheral ulcerative keratitis; pernicious anemia; pharmacological inflammatory response; pneumonia; prostatitis; psoriasis; psoriatic arthritis; reperfusion injury; rheumatic fever; rheumatoid arthritis; rhinitis; sarcoidosis; scleroderma; Sjogren's syndrome; systemic lupus erythematosus (SLE); transplant rejection syndrome; type I diabetes; type!! diabetes; vasculitis; and vitiligo.
[0009] Many of these diseases and conditions are severe and untreatable and as such cause distress and worry for the patients and their carers. As such, there remains a need in the art for an effective treatment for diseases and conditions associated with inflammation or autoimmunity.
[0010] The present invention provides evidence to show the compound of Formula!, 4-(6-oxo2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d] imidazol-8-yObenzonitrile, is effective in the treatment of diseases and conditions associated with inflammation or autoimmunity.
BRIEF SUMMARY OF THE DISCLOSURE
[0011] In accordance with a first aspect of the present invention there is provided a compound of Formula I for use in the treatment of diseases and conditions associated with inflammation or autoimmunity.
[0012] Preferably, the diseases or conditions associated with inflammation or autoimmunity is selected from the group consisting of Acne vulgaris; acute inflammation; Addison's disease; allergic reactions; allergies; Alzheimer's disease; ankylosing spondylitis; aplastic anemia; asthma; atherosclerosis; autoimmune vasculitis; cancer; celiac disease; chronic inflammatory demyelinating polyneuropathy (CI DP); chronic obstructive pulmonary disease (COPD); colitis; diverticulitis; endometriosis; familial Mediterranean fever; fatty liver disease; glomerulonephritis; Grave's disease; Guillain-Barre syndrome; Hashimoto's thyroiditis; headaches, including chronic headaches and migraine; hemolytic anemia; hidradenitis suppurativa; HIV and AIDS; hypersensitivity reactions; immune-mediated inflammatory disease (I MID); inflammatory bowel disease such as Crohn's disease and ulcerative colitis; inflammatory myopathies; interstitial cystitis; leukocyte defects; lichen planus; mast cell activation syndrome; mastocytosis; mental health conditions where inflammation and/or autoimmunity is a co-morbid or causative factor, including; depression, schizophrenia, and anxiety; multiple sclerosis; myasthenia gravis; obesity; otitis; pain, including acute and chronic pain; Parkinson's disease; pelvic Inflammatory disorder; peripheral ulcerative keratitis; pernicious anemia; pharmacological inflammatory response; pneumonia; prostafitis; psoriasis; psoriafic arthritis; reperfusion injury; rheumatic fever; rheumatoid arthritis; rhinitis; sarcoidosis; scleroderma; Sjogren's syndrome; systemic lupus erythematosus (SLE); transplant rejection syndrome; type I diabetes; type II diabetes; vasculitis; and vitiligo.
[0013] In some embodiments the diseases or condition associated with inflammation or autoimmunity is treatment resistant.
[0014] Preferably the compound of Formula I is administered with one or more pharmaceutically acceptable excipients.
[0015] Preferably the compound of Formula I is formulated in a dosage form selected from a liquid, a lozenge, a fast-disintegrating tablet, a lyophilized preparation, a film, a spray, an aerosol, a sustained-release tablet or capsule, a modified release, a sustained relief, a tablet, a capsule a cream, an ointment, or a mucoadhesive.
[0016] Preferably the compound of Formula I is administered as a single daily dose. Alternatively, the compound of Formula I is administered as multiple daily doses. Further still the compound is administered two, three, four or five times per day.
[0017] Preferably each dose comprises at least 0.001mg of the compound of Formula I. More preferably each dose comprises between about 0.001mg and about 500mg of the compound. Alternatively, each dose comprises between about 500mg and about 1000mg of the compound. [0018] In a further embodiment the compound is administered with one or more additional drug products.
[0019] In accordance with a second aspect of the present invention there is provided a method of treating diseases or conditions associated with inflammation or autoimmunity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I. [0020] In human therapeutics, the physician will determine the dosage regimen that is most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the disease and other factors specific to the subject to be treated. The compositions, in other embodiments, should provide a dosage of from about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, or about 1000 mg, and in some embodiments from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.
[0021] The amount of active ingredient in the formulations provided herein, which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.
[0022] Exemplary doses of a formulation include milligram or microgram amounts of the active compound per kilogram of subject (e.g., from about 1 microgram per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 microgram per kilogram to about 5 milligrams per kilogram).
[0023] It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.
[0024] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the above-described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.
[0025] In certain embodiments, administration of the same formulation provided herein may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
BRIEF SUMMARY OF THE DRAWINGS
[0026] The present invention is described with reference to the figure listed below: [0027] Figure 1 details the effect of compound of Formula I on NO release after 24h exposure.
[0028] Figure 2 details the effect of compound of Formula I on NO release after 5 days exposure.
[0029] Figure 3 details the standard competition curve of TNF-a.
[0030] Figure 4 details the effect of compound of Formula I on TNF-a release after 24h exposure [0031] Figure 5 details the standard competition curve of IL-113.
[0032] Figure 6 details the effect of compound of Formula I on IL-113 release after 24h exposure.
[0033] Figure 7 details the standard competition curve of IL-10.
[0034] Figure 8 details the effect of compound of Formula I on IL-10 release after 24h exposure
DEFINITIONS
[0035] Various definitions are made throughout this document. Most words have the meaning that would be attributed to those words by one skilled in the art. Words specifically defined either below or elsewhere in this document have the meaning provided in the context of the present invention as a whole and as typically understood by those skilled in the art.
[0036] "Subject," "individual" or "patient" is used interchangeably herein and refers to a vertebrate, preferably a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals and pets [0037] "Treating" or "treatment' of any disease or disorder refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof,). Treatment may also be considered to include preemptive or prophylactic administration to ameliorate, arrest or prevent the development of the disease or at least one of the clinical symptoms. Treatment can also refer to the lessening of the severity and/or the duration of one or more symptoms of a disease or disorder. In a further feature, the treatment rendered has lower potential for long term side effects over multiple years. In other embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In yet other embodiments, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter) or both. In yet other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder.
[0038] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, adsorption, distribution, metabolism and excretion etc., of the patient to be treated.
[0039] "Vehicle" refers to a diluent, excipient or carrier with which a compound is administered to a subject. In some embodiments, the vehicle is pharmaceutically acceptable.
[0040] "Active ingredient" or "Active pharmaceutical ingredient" or "API" refers to the compound of the invention or a pharmaceutically acceptable salt thereof.
[0041] "Inflammatory disease" and / or "Autoimmune disease" refers to any disease or condition which is caused by inflammation or autoimmunity. In particular the diseases and conditions associated with inflammation or auto-immunity of the invention include but are not limited to: Acne vulgaris; acute inflammation; Addison's disease; allergic reactions; allergies; Alzheimer's disease; ankylosing spondylitis; aplastic anemia; asthma; atherosclerosis; autoimmune vasculitis; cancer; celiac disease; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic obstructive pulmonary disease (COPD); colitis; diverticulitis; endometriosis; familial Mediterranean fever; fatty liver disease; glomerulonephrifis; Grave's disease; Guillain-Barre syndrome; Hashimoto's thyroiditis; headaches, including chronic headaches and migraine; hemolytic anemia; hidradenifis suppurafiva; HIV and AIDS; hypersensitivity reactions; immune-mediated inflammatory disease (I MID); inflammatory bowel disease such as Crohn's disease and ulcerative colitis; inflammatory myopathies; interstitial cystitis; leukocyte defects; lichen planus; mast cell activation syndrome; mastocytosis; mental health conditions where inflammation and/or autoimmunity is a co-morbid or causative factor, including; depression, schizophrenia, and anxiety; multiple sclerosis; myasthenia gravis; obesity; otitis; pain, including acute and chronic pain; Parkinson's disease; pelvic Inflammatory disorder; peripheral ulcerative kerafifis; pernicious anemia; pharmacological inflammatory response; pneumonia; prostatitis; psoriasis; psoriatic arthritis; reperfusion injury; rheumatic fever; rheumatoid arthritis; rhinitis; sarcoidosis; scleroderma; Sjogren's syndrome; systemic lupus erythematosus (SLE); transplant rejection syndrome; type I diabetes; type II diabetes; vasculitis; and vitiligo.
[0042] "Treatment resistant" is defined as the failure of a disease or disorder to respond positively or significantly to treatment.
[0043] "4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl) benzonitrile", also known as "CF3CN", referred to herein as the "compound of Formula l" has a SMILES code N#CC1=CC=C(C2=CC(C3=CC=C4C(N=C(C(F)(F)F)N4)=C302)=0)C=C1 and the structure defined below: Compound of Formula I *0
DETAILED DESCRIPTION OF THE INVENTION
[0044] The Examples below describe the use of the compounds of the invention in an in vitro and an in vivo Lipopolysaccharide (LPS)-induced cytokine secretion model.
[0045] The LPS model is an accurate and reliable model which involves the activation of circulating white blood cells, transmigration of these cells from the circulation to the peritoneal cavity, and the stimulation of these cells to release cytokines.
[0046] Another model that can be used to determine the anti-inflammatory properties of a compound is the Peripheral Blood Mononuclear Cell (PBMC) model. PBMCs are a variety of specialized immune cells that work together to protect our bodies from harmful pathogens and consist of lymphocytes and monocytes. PBMCs are extracted from whole blood using separation and then used to evaluate compounds for their anti-inflammatory activity.
EXAMPLE 1: INVESTIGATION OF THE NEUROPROTECTIVE EFFECT OF TEST COMPOUND ON DAMAGE INDUCED BY LPS ON CULTURE OF MESENCEPHALIC NEURONS [0047] The present study investigated the potential protective effect of the test compounds against LPS-mediated injury on mesencephalon neuronal-glia co-cultures.
Materials and Methods Drug preparation: [0048] The test compound was tested at 0.001, 0.01, 0.1, 1pM and 10pM. Stock solutions of the test compound was prepared 1000x to the highest tested concentration in 100% DMEM-F12 and was diluted in culture media.
[0049] Dexamethasone was used at 100nM as a positive control. Dexamethasone was prepared at 10mM in 100% DMSO. Aliquots were stored at -20°C until used.
[0050] BDNF was prepared at 100pg/m1 in sterile water. Aliquots were stored at -20°C until required. Stock solution was diluted in medium and used at 1Ong/ml.
Test animals: [0051] Pregnant VVistar rats (Janvier; France) were used for the study. They were housed and maintained in a room with controlled temperature (21-22°C) and a reversed light-dark cycle (12h/12h; lights on: 17:30 -05:30; lights off: 05:30 -17:30) with food and water available ad libitum.
Experimental design: [0052] The protocol was performed in 3 independent cultures. For each culture, each condition was performed in triplicate for read out at 24 hours after injury and in sextuplicate for read out at 5 days after injury. The major steps of the experiment are summarized in the table below: Day Tasks 0 Plating of a primary culture of rat embryo mesencephalic cells.
This culture contains microglia, astrocytes and neurons 2 Renewal of medium Renewal of medium 7 Compound application (1h before [PS injury) + [PS exposure 8 (24h post-LPS) Measure of nitric oxide (NO), TNF-a, 1[1-8 and IL-10 release 12 (day 5 post-[PS) Measure of release of NO in the supernatant [0053] The female rats were killed by cervical dislocation at 15 days gestation. Foetuses were removed from the uterus and their brains were harvested and placed in ice-cold medium (Leibovitz's L15 medium, Gibco). Only ventral mesencephalic flexure was used for the cell preparations. The midbrain was dissociated by trypsinization. The reaction was stopped, and the suspension was triturated and centrifuged. The pellet of dissociated cells is resuspended in culture medium consisted of DMEM-F12 (Gibco), containing 10% FBS (ATCC), 10% Horse serum (Gibco) and 2 mM L-glutamine (Gibco).
[0054] Viable cells were counted and seeded on 96-well plates, precoated with poly-L-lysine. Cells are maintained in a humidified incubator at 37°C in 5% CO2-95°/0 air atmosphere. [0055] Half of the medium was changed on days 2 and 5.
Treatment: [0056] On day 7, culture media were removed and replaced by new medium consisting of DMEM-F12 (Gibco) supplemented with 2% FBS (ATCC), 2% Horse serum (Gibco) and 2 mM Lglutamine (Gibco) and containing vehicle or test substance.
[0057] After 1-hour exposure, LPS at 50 ng/ml is added and exposure further continued for 24 hours or 5 days period. For each culture, plates for readout at 24 hours as well as sister plates for 5 days readouts were prepared at the same time.
[0058] In summary the following conditions were used: * No [PS (baseline group) * [PS + Vehicle (negative control group) * [PS + Dexamethasone (100 nM) (positive control group) * [PS + BDNF (10 ng/ml) * [PS + test compound 0.001 pM (1 nM) * [PS + test compound 0.01 pM (10 nM) * [PS + test compound 0.1 pM (100 nM) * [PS + test compound 1 pM * [PS + test compound 10 pM Inflammatory response measurement: [0059] NO production was measured in the media 24h and 5 days after [PS exposure using the Griess reagent kit (Molecular Probes). The Griess reagent Assay is a colorimetric reaction assay which measures the conversion of a sulfanilic salt into an azo dye product by nitrite. Visible wavelength absorbance data is collected using a 96-well plate reader at 570 nm (Mulfiskan EX, Thermo Fisher, France).
[0060] TNF-a release was measured in the media 24h after [PS exposure using the ELISA development kit (PeproTech). The ELISA plate, previously coated with anti-TNF-a antibody at 1 pg/ml, is incubated lh with PBS containing 1% of BSA (bovine serum albumin). After washing four times with PBS containing 0.05% of Tween-20, the plate was successively incubated 2h with supernatant, 2h with biofinylated antibody at 0.5 pg/ml in PBS containing 0.1% of BSA and 0.05% of Tween-20, 45 min with Avidin-HRP conjugated at 1/2000 and 30 min with colour ABTS substrate (Sigma). Visible wavelength absorbance data was collected using a 96-well plate reader at 405 nm with wavelength correction set at 650 nm (Multiskan EX, Thermo Fisher, France).
[0061] IL-1[3 and IL-10 release were measured in the media 24h after LPS exposure using the ELISA kit (R&D). For each cytokine, the ELISA plate was incubated 2h with supernatant with Assay Diluent RD1-21. After washing five times with wash buffer, the plate was successively incubated 2h with Rat IL-113 or IL-10 conjugate antibody and 30min with Substrate solution. After adding the stop solution, visible wavelength absorbance data was collected using a 96-well plate reader at 450 nm with wavelength correction set at 570 nm (Multiskan EX, Thermo Fisher, France).
Statistical analysis: [0062] The drug-induced effect on NO was calculated by setting the response of the [PS-stimulated control as 100% and expressed as % of difference between OD values. The drug-induced effect on cytokines was calculated using the Standard curve and expressed as pg/ml. [0063] The drug-induced effect on TH-positive neurons was measured by setting the number recorded under non-intoxicated culture condition as 100%.
[0064] The standard curve of the three cytokines was plotted using non-linear regression by GraphPad prism software. The concentration of the cytokines in each sample was extrapolated using this standard curve in the range of concentration (Table 1) and was expressed in pg/ml. For graph and statistics, sample detected below or above the limit of detection was replaced by the respective limit.
Table 1 Range of cytokines/chemokines detection by the ELISA kits Range (pg/ml) TNF-a 24 to 3000 IL-1I3 31.3 to 2000 IL-10 31.3 to 2000 [0065] Analysis of data was performed using analysis of variance (ANOVA). The Fisher's Protected Least Significant was used for multiple comparisons. p value.s 0.05 was considered significant. The software used was StatView 5.0 (SAS Institut).
[0066] The drug-induced effect on NO was calculated by setting the response of the [PS-stimulated control as 100%.
Results Effect on NO release after 24h [0067] As shown in Figure 1, 24h stimulation of cultures with LPS (50 ng/ml) induced a substantial increase in NO release compared to the non-stimulated cultures (vehicle group, p<1.0001).
[0068] As expected, Dexamethasone (100 nM) elicited a significant decrease in the LPSinduced NO release in the mesencephalic cultures. The decrease was about 86% compared to the activity measured in the LPS-stimulated control (ps0.0001).
[0069] The compound of Formula! at 10 pM induced a slight decrease of about 17% of NO release compared to the LPS treated group (p=0.0012).
[0070] BDNF at 1Ong/m1 had no effect on [PS-induced NO release.
Effect on NO release after 5 days [0071] After 5 days exposure to [PS (50 ng/ml), NO release remained substantial compared to the non-stimulated condition (ps0.0001) (Figure 2).
[0072] Dexamethasone (100 nM) elicited a significant decrease in the LPS-induced NO release in the mesencephalic cultures (Figure 2). The decrease was about 86% compared to the activity measured in the [PS-stimulated control (ps0.0001).
[0073] The compound of Formula! at 1pM induced a slight but significant increase of about 13% of NO release compared to the LPS treated group (p=0.0102).
[0074] BDNF at 1Ong/m1 had no effect on [PS-induced NO release.
Effect on TNF-a release after 24h [0075] The dose response curve for TNF-a is shown in Figure 3.
[0076] The TNF-a level in vehicle group was about 53 pg/ml in the supernatant (Figure 4). [0077] After 24h exposure, [PS (50ng/m1) induced a significant increase in TNF-a release of about 1182 pg/ml in mesencephalic cultures compared to non-stimulated cultures (ps0.0001, Figure 4).
[0078] As expected, Dexamethasone (100 nM) reduced the production of TNF-a induced by [PS by about 79 °A) (ps0.0001).
[0079] The compound of Formula I induced a significant decrease of [PS-induced TNF-a release. The decrease was maximal at a concentration of 100nM and was about 26% compared to the level in [PS stimulated control (p50.0001).
[0080] BDNF at 1Ong/m1 induced a slight but significant reduction of [PS-induced 1L-113 release. This reduction was about 12% compared to the level in [PS-stimulated control (p=0.0414).
Effect on 1L-18 production after 24h [0081] The dose response curve for1L-113 is shown in Figure 5.
[0082] 1L-18 level in vehicle group was about 32 pg/ml in the supernatant (Figure 6).
[0083] After 24h exposure, [PS (50ng/m1) induced a significant increase in 1L-113 release of about 199 pg/ml in mesencephalic cultures as compared to non-stimulated cultures (p50.0001, Figure 6) [0084] As expected, Dexamethasone (100 nM) reduced the production of IL-1[3 induced by LPS by about 84% (p0.0001).
[0085] The compound of Formula I at 1 and 10nM had no significant effect on LPS-induced IL-1p release. In contrast, the compound of Formula I at 0.1, 1 and 10 pM induced a significant increase in 1L-113 release as compared to LPS-stimulated control. The 1L-1p release was 141, 148 and 146%, respectively, as referred to the level in LPS-stimulated control (p=0.0005, p.s0.0001 and p=0.0002, respectively).
[0086] BDNF at 1Ong/m1 had no effect on LPS-induced 1L-113 release.
Effect on IL-10 release after 24h [0087] The dose response curve for IL-10 curve is shown in Figure 7.
[0088] IL-10 level in vehicle group was about 32 pg/ml in the supernatant (Figure 8).
[0089] After 24h exposure, LPS (50ng/m1) induced a significant increase in IL-10 release of about 202 pg/ml in mesencephalic cultures as compared to non-stimulated cultures (p<).0001, Figure 8).
[0090] Dexamethasone 000 nM) increased the production of IL-10 induced by LPS by about 159 % (p<).0001).
[0091] The compound of Formula I at 1 and 10pM induced a significant increase in the IL-10 release as compared to LPS-stimulated control (p=0.0265 and p<).0001, respectively). The reduction of IL-10 release was about 15 and 30%, respectively, as referred to the level in LPSstimulated control.
[0092] BDNF at 1Ong/m1 had no effect on LPS-induced IL-10 release.
Conclusion
[0093] Example 1 was conducted to evaluate the potential protective effect of the compound of Formula I against inflammation and neuronal death induced by LPS in mesencephalic cultures containing microglia, astrocytes and neurons. The 24h release of NO, 1L-113, INF-a and IL-i0, in the culture media was the marker of inflammation quantified.
[0094] Significant results from the study are briefly described below.
[0095] As would be expected LPS induced an increase of NO, TNF-a, IL-1p and IL-10 releases and of neuronal death in mesencephalic cultures.
[0096] The compound of Formula I at a concentration of 10pM produced a small (-17%) but significant decrease in LPS-induced NO release (24h).
[0097] The compound of Formula I at concentrations of 10, 100nM and 1 pM produced a significant decrease in TNF-a release with a maximal effect at 100nM (-26%).
[0098] The compound of Formula I at concentrations of 0.1 to 10pM produced a significant increase in IL-113 release (141, 148 and 146%, respectively).
[0099] The compound of Formula I induced a decrease in LPS-induced IL-10 release with maximal effect obtained at the concentration of 10 pM (-30%).
[00100] The positive control, dexamethasone, tested in parallel produced 86, 79 and 84% inhibition of NO, pro-inflammatory cytokines TNF-a and IL-1p releases, respectively, and 202% increase of anti-inflammatory cytokines IL-10 release.
[00101] BDNF (10ng/m1) had no effect on NO, IL-1I3 and IL-10 releases but induced a slight but significant decrease in TNF-a release of about 12%.
[00102] Therefore, the compound of Formula I reduced the release of NO after 24h LPS exposure, TNF-a and IL-10 elicited by the LPS stimulation.
[00103] Taken together these data provide evidence that the compound of Formula I would be useful in the treatment of diseases and conditions associated with inflammation and auto-immunity.
Claims (10)
- CLAIMS1. The compound of Formula I for use in the treatment of diseases and conditions associated with inflammation or autoimmunity.
- The compound of Formula I for use according to claim 1, wherein the diseases or conditions associated with inflammation or autoimmunity is selected from the group consisting of: Acne vulgaris; acute inflammation; Addison's disease; allergic reactions; allergies; Alzheimer's disease; ankylosing spondylitis; aplastic anemia; asthma; atherosclerosis; autoimmune vasculifis; cancer; celiac disease; chronic inflammatory demyelinating polyneuropathy (Cl DP); chronic obstructive pulmonary disease (COPD); colitis; diverticulitis; endometriosis; familial Mediterranean fever; fatty liver disease; glomerulonephritis; Grave's disease; Guillain-Barre syndrome; Hashimoto's thyroiditis; headaches, including chronic headaches and migraine; hemolytic anemia; hidradenifis suppurativa; HIV and AIDS; hypersensitivity reactions; immune-mediated inflammatory disease (IMID); inflammatory bowel disease such as Crohn's disease and ulcerative colitis; inflammatory myopathies; interstitial cystitis; leukocyte defects; lichen planus; mast cell activation syndrome; mastocytosis; mental health conditions where inflammation and/or autoimmunity is a co-morbid or causative factor, including; depression, schizophrenia, and anxiety; multiple sclerosis; myasthenia gravis; obesity; otitis; pain, including acute and chronic pain; Parkinson's disease; pelvic Inflammatory disorder; peripheral ulcerative keratitis; pernicious anemia; pharmacological inflammatory response; pneumonia; prostatitis; psoriasis; psoriatic arthritis; reperfusion injury; rheumatic fever; rheumatoid arthritis; rhinitis; sarcoidosis; scleroderma; Sjogren's syndrome; systemic lupus erythematosus (SLE); transplant rejection syndrome; type I diabetes; type II diabetes; vasculitis; and vitiligo.
- 3. The compound of Formula I for use according to claim 1, wherein the diseases or condition associated with inflammation or autoimmunity is treatment resistant.
- The compound of Formula I for use according to claim 1, wherein the compound is administered with one or more pharmaceutically acceptable excipients.
- 5. The compound of Formula I for use according to claim 1, wherein the compound is formulated in a dosage form selected from a liquid, a lozenge, a fast-disintegrating tablet, a lyophilized preparation, a film, a spray, an aerosol, a sustained-release tablet or capsule, a modified release, a sustained relief, a tablet, a capsule a cream, an ointment, or a mucoadhesive.
- The compound of Formula I for use according to claim 1, wherein the compound is administered as a single daily dose.
- The compound of Formula I for use according to claim 1, wherein the compound is administered as multiple daily doses.
- 8. The compound of Formula I for use according to claims 7 or 8, wherein each dose comprises at least 0.001mg of the compound.
- The compound of Formula I for use according to claim 1, wherein the compound is administered with one or more additional drug products.
- 10. A method of treating diseases or conditions associated with inflammation or autoimmunity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of Formula I.
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| PCT/GB2023/053029 WO2024110744A1 (en) | 2022-11-22 | 2023-11-20 | 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile for use in the treatment of diseases and conditions associated with inflammation or autoimmunity |
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| WO2023227881A1 (en) * | 2022-05-24 | 2023-11-30 | Ontrack Therapeutics Limited | Compounds for use in the treatment of diseases and conditions associated with neurodegenerative dysfunction |
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- 2022-11-22 GB GB2217453.6A patent/GB2624633A/en active Pending
-
2023
- 2023-11-20 WO PCT/GB2023/053029 patent/WO2024110744A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020033604A1 (en) * | 2018-08-07 | 2020-02-13 | Emory University | Heterocyclic flavone derivatives, compositions, and methods related thereto |
Non-Patent Citations (8)
| Title |
|---|
| ACS Chemical Neuroscience, vol. 12, 2021, Chen et al. "Optimized TrkB agonist ameliorates Alzheimer's disease pathologies and improves cognitive functions via inhibiting delta-secretase", pages 2448-2461 [Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269693/] * |
| International Journal of Molecular Medicine, vol. 29, 2012, Park et al. "7,8-dihydroxyflavone exhibits anti-inflammatory properties by downregulating the NF-kB and MAPK signaling pathways in lipopolysaccharide-treated RAW264.7 cells", pages 1146-1152 * |
| International Journal of Molecular Medicine, vol. 33, 2014, Park et al. "7,8-Dihydroxyflavone attenuates the release of pro-inflammatory mediators and cytokines in lipopolysaccharide-stimulated BV2 microglial cells through suppression of the NF-kB and MAPK signaling pathways", pages 1027-1034 * |
| International Journal of Neuropsychopharmacology, 2015, Zhang et al. "Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation", pages 1-12 [Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360225/] * |
| Journal of Pharmacy and Pharmacology, vol. 69, 2017, Jin et al. "Inhibition of pro-inflammatory mediators in RAW264.7 cells by 7-hydroxyflavone and 7,8-dihydroxyflavone", pages 865-874 * |
| Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 388, No. 1, 2015, Stöckel et al. "Antiinflammatory effect of 7,8-dihydroxyflavone (7,8-DHF) on microglia", page S31 * |
| Neuropharmacology, vol. 197, 2021, Liao et al. "Targeting both BDNF/TrkB pathway and delta-secretase for treating Alzheimer's disease", pages 1-26 [Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478860/] * |
| Neurotherapeutics, vol. 19, 2022, Kang et al. "Treating Parkinson's disease via activation of BDNF/TrkB signalling pathways and inhibition of delta-secretase", pages 1283-1397 [Available from: https://link.springer.com/article/10.1007/s13311-022-01248-1] * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024110744A1 (en) | 2024-05-30 |
| GB202217453D0 (en) | 2023-01-04 |
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