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WO2019038156A1 - Utilisation d'un antagoniste d'ep4 pour le traitement de l'arthrite - Google Patents

Utilisation d'un antagoniste d'ep4 pour le traitement de l'arthrite Download PDF

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Publication number
WO2019038156A1
WO2019038156A1 PCT/EP2018/072132 EP2018072132W WO2019038156A1 WO 2019038156 A1 WO2019038156 A1 WO 2019038156A1 EP 2018072132 W EP2018072132 W EP 2018072132W WO 2019038156 A1 WO2019038156 A1 WO 2019038156A1
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Prior art keywords
arthritis
inhibitors
compound
treatment
rheumatic diseases
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Alexandra RAUSCH
Jens Nagel
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Bayer Pharma AG
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Bayer Pharma AG
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the use of an EP4 antagonist for the treatment and/or prophylaxis of arthritis especially rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, as well as other immune-mediated rheumatic diseases, and/or other pathological conditions associated with increased activation of EP4 receptors by prostaglandin E2 (PGE2).
  • PGE2 prostaglandin E2
  • Arthritis is not a single disorder, but is a common term for immune-mediated rheumatic diseases, which comprise a group of more than 100 diseases that affect the joints, like for instance rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Arthritis is characterized by progressive inflammation, severe pain, swelling and stiffness of the affected synovial joints (Koenders & van den Berg, 2016). Whereas RA mainly affects the joints in a symmetrical manner and is often associated with production of autoantibodies (e.g. rheumatoid factor), PsA and AS are considered as seronegative rheumatic diseases.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriatic arthritis
  • a characteristic hallmark of arthritis is the activation of immune cells that target self-tissue leading to inflammation upon production of pro-inflammatory cytokines.
  • immune cells e.g. antigen-presenting cells like dendritic cells and monocytes/macrophages
  • T cells, B cells further immune cells
  • hyperplasia of the normally thin synovial membrane occurs and fluid collects in the narrow joint space causing swelling and impaired mobility (Firestein, 2003).
  • the arising joint inflammation can differ in the severity between patients, but is chronic and progressive in nature causing joint damage and bone erosion (Pablos and Canete, 2013).
  • Nonsteroidal antiinflammatory drugs are used to reduce pain and inflammation in arthritis and represent an effective therapy (Koenders & van den Berg, 2016).
  • NSAIDs nonsteroidal antiinflammatory drugs
  • MTX methotrexate
  • TNF tumor necrosis factor
  • the receptor EP4 (PTGR 4 ) is one of the 4 human receptors that are activated by endogenously formed prostaglandin E2 (PGE2).
  • EP4 belongs to the family of membrane- bound G-protein coupled receptors (GPCR) and is mainly provided with a Gs coupling, which after activation leads to an accumulation of the intracellular signal molecule cyclic AMP (cAMP).
  • GPCR membrane- bound G-protein coupled receptors
  • cAMP intracellular signal molecule cyclic AMP
  • TH17 T helper 17 cells
  • PGE2 PGE2 to its EP4 receptor participates and promotes TH 17 cell differentiation/maturation, expansion and function ⁇ Yao, Sakata, Esaki et al., 2009; Boniface et al., 2009; Sheibanie et al., 2004; Khayrullina et al., 2008).
  • PGE2 thereby increases the IL-17 production from TH17 cells through the EP2/EP4 - cAMP signaling pathway ⁇ Yao, Sakata, Esaki et al., 2009; Boniface et al., 2009). Furthermore, PGE2-EP4 signaling indirectly promotes TH17 cell expansion, due to the fact that it stimulates interleukin (IL)-23 production by dendritic cells ⁇ Yao, Sakata, Esaki et al., 2009; Chizzolini et al., 2008; Boniface et al., 2009; Napolitani et al., 2009). Next to this, Sheibanie et al.
  • IL interleukin
  • PGE2 exacerbates collagen-induced arthritis in mice via the IL-23/IL-17 axis ⁇ Sheibanie, Khayrullina, Safadi, Ganea et al. 2007). Additionally, PGE2 has been associated with the edema and the erosion of cartilage and bone in arthritis ⁇ McCoy, Wicks, Audoly, 2002). Furthermore, it has been shown by McCoy et al. that EP4 receptor-deficient mice show a decreased incidence and severity of arthritis related to reduced IL-6 and serum amyloid A levels.
  • EP4 antagonists of different structural classes have been described, Thus in WO20050121508, WO2005102389 and WO2005105733 (Pfizer), for example, /V-benzylarylamides, N- benzylheteroarylamides and [(1 H-benzimidazol-1 -yl)phenylethyl]aryl- and [(1 H-benzimidazol- 1 -yl)phenylethyl]heteroarylsulphonylcarbamates are described for use in the case of pain, inflammation, osteoarthritis and rheumatoid arthritis.
  • Pfizer also describes in WO2002032422, WO2002032900 and WO2003086371 structures that include generic benzimidazoles.
  • Thiophene-/V-benzylamides in WO2008017164 and WO2009020588, indole-N-benzylamides in WO2007121578 and N- ⁇ [(6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7- yl)-aryl]methyl ⁇ sulphonylamides in WO2008104055 are addressed for nearly the same indication spectrum by Merck-Frosst.
  • WO2004067524 Pulsagene Laboratories
  • furan derivatives for the treatment of headache and migraine are described.
  • EP2172447 (Astellas Pharma) claims generically in a very broad manner compounds that can consist of two heterocycles connected directly to one another, for the indications renal insufficiency and diabetic nephropathy.
  • the underlying problem of the present invention therefore lies in the provision of medication for treatment of arthritis especially rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, as well as other immune-mediated rheumatic diseases and/or other pathological conditions associated with increased activation of EP4 receptors by prostaglandin E2 (PGE2).
  • PGE2 prostaglandin E2
  • Fig. 1 is a highly potent, competitive human EP4 receptor antagonist with inverse agonist activity.
  • Secondary in vitro assays revealed a high functional potency on EP4 receptors of mouse, rat and cynomolgus.
  • Compound 1 was highly active in inhibiting the PGE2-mediated augmentation of IL-17 secretion during maturation of TH17 cells in vitro (Fig. 2).
  • compound 1 showed robust efficacy in murine arthritis studies in vivo.
  • the compound attenuated the disease severity, which was assessed by the disease activity score (Fig. 3), as well as the joint swelling (Fig. 4).
  • This anti-inflammatory reduction in the in- life parameters after treatment with compound 1 were confirmed by histopathological evaluation of joints (Fig. 6).
  • hyperalgesia was reduced by treatment with compound 1 in arthritic rats (Fig. 5).
  • Evaluation of clinical relevant pro-inflammatory biomarkers revealed an inhibition of the erythrocyte sedimentation rate (ESR), the levels of CRP (C-reactive protein) and the cytokine IL-6 after treatment with compound 1 during experimental arthritis (Fig. 7 A, B, C).
  • compound 1 for the treatment of arthritis especially rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, as well as other immune-mediated rheumatic diseases, and/or other pathological conditions associated with increased activation of EP4 receptors by prostaglandin E2 (PGE2) provides a solution for the underliying problem of the invention.
  • PGE2 prostaglandin E2
  • This figure shows the binding characteristics of compound 1 .
  • Experiments were performed to show that the binding is antagonistic (Part A), agonistic (part B) or inverse agonistic (Part C).
  • the results show that compound 1 is a highly potent, competitive human EP4 receptor antagonist with inverse agonist activity.
  • figure 1A square (A), B (triangle), C (circle) and D (diamond) show the results of the same experiment.
  • Total CD4 + T cells isolated from human PBMCs were stimulated with anti-CD3/anti-CD28 plus IL-23 in the presence or absence of exogenous PGE2 and compound 1 for 3 days.
  • Compound 1 was applied to stimulated cell culture in the indicated concentrations ranging from 1 pM up to 1 ⁇ . Data are shown as means ⁇ SD. These data from one donor are representative of at least four independent donors.
  • Statistical analysis was performed by ANOVA with Dunett ' s Test, * p ⁇ 0.05; ** p ⁇ 0.01 ; *** p ⁇ 0.005; **** p ⁇ 0.001 compared with anti-CD3/anti-CD28 + IL-23 + PGE2-stimulated CD4 + T cells. (rhlL-23 stands for recombinant human IL-23).
  • Figure 5 Inhibitory effect of compound 1 on hyperalgesia by increase of grip strength in rat AIA
  • Hyperalgesia measured via loss of grip strength, was detected by a grip strength test meter before the arthritis induction (day 0) and afterwards on days 8, 10, 13, 15, 17 and 20.
  • Figure 6 represents the significant efficacy of compound 1 treatment with regard to the prevention of joint destruction after blinded evaluation of the joint histopathology in AIA rats.
  • Figure 7 Anti-inflammatory effects of compound 1 on inflammatory biomarkers in rat AIA model
  • ESR Erythrocyte sedimentation rate
  • CRP C-reactive protein
  • QD p.o. dark grey triangle
  • the data presented in several in vitro and in vivo models demonstrates the effectiveness of compound 1 for treatment and/or prophylaxis of arthritis especially rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, as well as other immune-mediated rheumatic diseases, and/or other pathological conditions associated with increased activation of EP4 receptors by prostaglandin E2 (PGE2).
  • PGE2 prostaglandin E2
  • the present invention is based on the discovery that compound 1 (2-(9-Ethyl-6-methyl-9H- carbazol-3-yl)-1 -(2-methoxyethyl)-4-methyl-1 H-benzimidazole-5-carboxylic acid) is highly potent in the treatment of arthritis especially rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, as well as other immune-mediated rheumatic diseases, and/or other pathological conditions associated with increased activation of EP4 receptors by prostaglandin E2 (PGE2).
  • PGE2 prostaglandin E2
  • subject matter of the present invention is directed to the use of compound 1 for treatment of arthritis especially rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, as well as other immune-mediated rheumatic diseases, and/or other pathological conditions associated with increased activation of EP4 receptors by prostaglandin E2 (PGE2).
  • PGE2 prostaglandin E2
  • the therapeutically active dose is dependent on the body weight, administration route, individual behaviour, and the type of preparation and time or interval at which administration takes place.
  • a typical dose range for a woman of 70 kg body weight is between 1 -500 mg/day, preferably between 5 and 30 mg/day.
  • a further subject of the present invention relates to medicaments containing compound 1 according to the invention and at least one or more other active substances, in particular for the treatment and/or prophylaxis of arthritis.
  • active substances that may be mentioned by way of example and preferably are: inhibitors of mitogen activated protein (MAP) kinase and inhibitors of MAP kinases (Mkk3/6, Mek1/2, Erk1/2), inhibitors of protein kinases B ( ⁇ / ⁇ / ⁇ ; Akt1/2/3), inhibitors of phosphoinositide-3 kinase (PI3K), inhibitors of cyclin-dependent kinase (CDK1/2), Inhibitors of the hypoxia-induced signal pathway (HIF1 alpha inhibitors, activators of the prolylhydroxylases), histone deacetylase (HDAC) inhibitors, prostaglandin F receptor (FP) (PTGFR) antagonists, neurokinin 1 receptor antagonists, paracetamol, selective COX2 inhibitors and/or non-selective COX
  • Humira® etanercept, infliximab, certolizumab
  • IL-1 inhibitors e.g. anakinra, canakinumab, rilonacept
  • IL-17 inhibitors e.g. secukinumab, brodalumab, ixekizumab
  • IL-6/IL-6 receptor antagonists e.g. tocilizumab, sarilumab, siltuximab
  • IL-12/IL- 23 inhibitors e.g. ustekinumab
  • phosphodiesterase inhibitors e.g.
  • Compound 1 can be employed for the treatment of arthritis especially rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, both after oral as well as parenteral administration.
  • Compound 1 according to the invention can act systemically and/or locally.
  • it can be administered in a suitable manner, such as e.g. orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compound according to the invention can be administered in suitable administration forms.
  • the dosage of compound 1 in these preparations should be 0.01 % - 20 %, in order to achieve an adequate pharmacological action.
  • the dosage of the active substances can vary, depending on administration route, age and weight of the patient, nature and severity of the disease to be treated and similar factors.
  • the treatment can be carried out by means of individual doses or by a plurality of doses over a relatively long period.
  • the amount per day is approximately 0.01 to 100 mg/kg of body weight.
  • the amount of compound 1 to be administered varies within a wide range and can cover any effective amount.
  • a typical dose range for a woman of 70 kg body weight is between 1 - 500 mg/day, preferably between 5 and 30 mg/day. Nevertheless, it can optionally be necessary to deviate from the amounts mentioned, namely, depending on body weight, administration route, individual behaviour towards the active substance, nature of the preparation and time or interval at which administration takes place.
  • surface-active excipients such as salts of the bile acids or animal or vegetable phospholipids can also be used, but also mixtures thereof and liposomes or their constituents.
  • releasing compound 1 to be used according to the invention rapidly and/or in modified form which contain compound 1 according to the invention in crystalline and/or amorphized and/or dissolved form
  • suitable such as, e.g., tablets (non-coated or coated tablets, for example, having enteric or slowly dissolving or insoluble coatings, which control the release of the compound to be used according to the invention), tablets or films/wafers disintegrating rapidly in the oral cavity, films/lyophilizates, capsules (for example, hard or soft gelatine capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can take place circumventing an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with inclusion of an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • an absorption step e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbarly
  • an absorption e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally
  • suitable administration forms are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • compositions for inhalation e.g., pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nose drops, solutions or sprays, tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, ear or eye preparations, tinctures, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, crystal suspensions, aqueous and oily injection solutions, depot preparations, ointments, fatty ointments, gels, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants, or stents are suitable.
  • pharmaceutical forms for inhalation inter alia powder inhalers, nebulizers
  • nose drops solutions or sprays
  • tablets to be administered lingually, sublingually or buccally films/wafers or capsules, suppositories, ear or eye preparations, tinctures,
  • Oral or parenteral administration is preferred, in particular oral and intravenous administration.
  • Topic application is also an option.
  • Compound 1 to be used according to the invention can be converted into the administration forms mentioned. This can take place in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable excipients.
  • excipients include, inter alia, carrier substances (for example, microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binding agents (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colourants (e.g. inorganic pigments such as, for example, iron oxides) and taste and/or odour corrigents.
  • carrier substances for example, microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • a further subject of the present invention is a medicament that contains compound 1 according to the invention, customarily together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the previously mentioned purposes.
  • the percentages in the following tests and examples are, if not stated otherwise, percentages by weight; parts are parts by weight.
  • Solvent ratios, dilution ratios and concentrations of liquid/liquid solutions in each case relate to the volume.
  • the subject matter of the present invention is also directed to a method for alleviating pathological conditions associated with PGE2 induced increased EP4 receptors activation by antagonising the activation of EP4 receptors by compound 1.
  • Binding of PGE2 to the Gas coupled human EP4-receptor leads to the stimualtion of adenylate cyclase activity and the formation of cAMP.
  • the amount of cAMP produced following agonist stimulation is detected with the help of a competition assay based on a fluorescently labelled cAMP tracer (cAMP-d2) and Eu-cryptate labelled anti-CAMP antibody.
  • Maximum signal obtained via fluorescence resonance energy transfer; FRET
  • FRET fluorescence resonance energy transfer
  • Table 1 represents the steps of assay ready cells from frozen cell stocks.
  • hEP4-R stably transfected into HEK cells (clone hEP4-C1 cells), Read plates: Polystyrol; 384well, SV white, Greiner # 784075, Dimethylsulphoxide, DMSO: Sigma-Aldrich # D-2650, 3-lsobutyl-1 -methylxanthine, IBMX: Sigma-Aldrich # 1-7018, cAMP HTRF-Assay Kit: Cisbio International 62AM6PEJ high range.
  • Step 1 Reconstitution of both, cAMP-d2 & anti-CAMP cryptate with water (5 ml) according to suppliers manual.
  • Step 2 Further 1 :39 dilution with Conjugate & Lysisbuffer.
  • Conjugate & Lysisbuffer prepared according to cAMP kit protocol (Cisbio).
  • compound 1 is a highly potent, competitive human EP4 receptor antagonist with inverse agonist activity.
  • EXAMPLE 3 in vitro IL-17 inhibition experiments in stimulated human TH17 cells
  • cytokine IL-17 interleukin-17, synonyme IL-17A
  • IL-17A pro-inflammatory cytokine IL-17
  • human CD4 + T cells were used.
  • PBMCs peripheral blood mononuclear cells
  • Histopaque ® -1077 Sigma, # 1077-1
  • plasma including thrombocytes was discarded.
  • the mononuclear cell layer (PBMCs) was carefully collected and washed three times with PBS (phosphate buffered saline; w/o Ca 2 7Mg 2+ ) (Gibco, # 14190-094).
  • PBMCs were resuspended in culture medium (RPMI 1640 GlutaMax [Gibco, # 61870], supplemented with 10% FCS (fetal calf serum), 50 U/ml Penicillin and 50 g/ml Streptomycin [PAA, # P1 1 -010]).
  • RPMI 1640 GlutaMax Gibco, # 61870
  • FCS fetal calf serum
  • PAA 50 g/ml Streptomycin
  • CD4 + T cells were isolated out of PBMCs by magnetic cell separation (CD4+ T cell Isolation Kit, Miltenyi Biotech, # 130-096-533) via a column (LS column, Miltenyi Biotech, # 130-042-401 ).
  • Total CD4 + T cells were plated in 1 x10 5 cells/well in a flat bottom 96-well microtiter plate (Costar, # 3599).
  • Compound 1 was serial diluted out of a constant volume of 100% DMSO and was used in 8 different concentrations (from 1 ⁇ to 1 pM) in the stimulation assay. Each of the 8 tested concentrations contained 0.1 % DMSO.
  • human CD4 + T cells were differentiated over 3 consecutive days towards IL-17-producing TH17 cells by adding a recombinant human (rh) IL-23 (10 ng/ml; eBioscience, # 14-8239-63) and the activation stimulus with plate-bound anti-CD3 (5 ⁇ g ml; purified mouse monoclonal lgG1 ; R&D Systems, # MAB100) and anti-CD28 (1 g/ml; purified mouse monoclonal lgG1 ; R&D Systems, # MAB342) in the presence or absence of PGE2 (10 nM; Cayman, # 14010).
  • rh human (rh) IL-23
  • plate-bound anti-CD3 5 ⁇ g ml; purified mouse monoclonal lgG1 ; R&D Systems, # MAB100
  • anti-CD28 (1 g/ml; purified mouse monoclonal lgG1 ; R&D Systems, # MAB342
  • CFA complete Freund ' s adjuvant
  • CFA complete Freund's adjuvant
  • Compound 1 was once daily (QD) applied per os (p.o.) from day 0 onwards in different dosages (0.2 mg/kg, 1 mg/kg and 5 mg/kg or 2.5 mg/kg and 5 mg/kg) using an appropriate vehicle (0.5% CMC [carboxylmethyl cellulose] in water; m/v), which allowed sufficient exposure of the animals with the compound.
  • the disease activity score was determined for both hind paws and added up. Furthermore, both hind paw volume using a plethysometer (IITC Life Science Inc., USA) and joint thickness (sagittal x transversal in mm 2 , hind paws) were detected. Next to this, grip strength as indicator for hyperalgesia was analysed by using an automated grip strength test meter (IITC Life Science Inc., USA). At the end of the study (day 20) blood serum was collected and analysed for pro- inflammatory biomarkers (e.g. CRP, BD Biosciences, # 55825; ESR).
  • pro- inflammatory biomarkers e.g. CRP, BD Biosciences, # 55825; ESR.
  • joint biopsies were obtained and the extent of joint damage was evaluated by histopathology using a scoring system grading synovial hyperplasia, immune cells infiltration, erosion of cartilage/bone, etc..
  • pro-inflammatory cytokines were analysed in the joint biopsies after generation of tissue extracts via pulverization of joints with a cryomill at minus 196°C (CryoMill; Retsch GmBH, Germany).
  • 200 mg of joint tissue extract were mixed with 0.5 ml RPMI 1640 medium (Gibco, #61870) for cytokine analysis (Proinflammatory Panel 1 ; Mesoscale, # K15059D-1 ).
  • Statistical analysis of data was performed by using one-way ANOVA (Analysis of variance) and multiple comparisons to the disease control group via the Dunnett ' s test.
  • compound 1 for the treatment of arthritis especially rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, as well as other immune-mediated rheumatic diseases, and/or other pathological conditions associated with increased activation of EP4 receptors by prostaglandin E2 (PGE2) is subject matter of the present invention.
  • PGE2 prostaglandin E2
  • Still ' s disease crystall-induced arthritis (like gout), fibromyalgia, osteoarthritis, and rheumatic diseases caused by autoimmunity (e.g. systemic lupus erythematosus, relapsing polychondritis, polymyositis, Behcet ' s disease, Sjogren syndrome, scleroderma).
  • autoimmunity e.g. systemic lupus erythematosus, relapsing polychondritis, polymyositis, Behcet ' s disease, Sjogren syndrome, scleroderma.
  • a medicament comprising compound 1 in combination with one or more further active compounds, especially with immunomodulatory and immunosuppressive compounds such as cyclosporine, Methotrexat® (MTX), Jak/STAT inhibitors (e.g Baricitinib, Tofacitinib, GLPG0634), TNF antagonists (e.g. Humira®, etanercept, infliximab, certolizumab), IL-1 inhibitors (e.g. anakinra, canakinumab, rilonacept), IL-17 inhibitors (e.g.
  • immunomodulatory and immunosuppressive compounds such as cyclosporine, Methotrexat® (MTX), Jak/STAT inhibitors (e.g Baricitinib, Tofacitinib, GLPG0634), TNF antagonists (e.g. Humira®, etanercept, infliximab, certolizumab), IL-1 inhibitors (e.
  • IL-6/IL-6 receptor antagonists e.g. tocilizumab, sarilumab, siltuximab
  • IL-12/IL-23 inhibitors e.g. ustekinumab
  • phosphodiesterase inhibitors e.g. Apremilast®
  • leflunomid teriflunomid
  • cyclophosphamide rituximab
  • belimumab tacrolimus
  • rapamycin mycophenolate mofetil
  • corticosteroids e.g.
  • NSAIDS nonsteroidal anti-inflammatory substances
  • MAP mitogen-activated protein
  • PI3K inhibitors of phosphoinositide 3-kinase
  • CDK1/2 inhibitors of cyclin- dependent kinase
  • HDAC histone deacetylase
  • medicaments comprising compound 1 in combination with an inert, nontoxic, pharmaceutically suitable auxiliary.
  • Also subject matter of the present invention is a medicament comprising compound 1 for the treatment of arthritis especially rheumatoid, ankylosing spondylitis, psoriatic arthritis, as well as other other immune-mediated rheumatic diseases selected from a list comprising of infectious arthritis (like Lyme disease, reactive arthritis, PAPA syndrome), juvenile rheumatoid arthritis (e.g. Still ' s disease), crystall-induced arthritis (like gout), fibromyalgia, osteoarthritis, and rheumatic diseases caused by autoimmunity (e.g. systemic lupus erythematosus, relapsing polychondritis, polymyositis, Behcet ' s disease, Sjogren syndrome, scleroderma).
  • infectious arthritis like Lyme disease, reactive arthritis, PAPA syndrome
  • juvenile rheumatoid arthritis e.g. Still ' s disease
  • crystall-induced arthritis like gout
  • compound 1 in the form of a pharmaceutical preparation for enteral, parenteral, topical and oral administration.
  • Also subject matter of the present invention is a method for alleviating pathological conditions associated with PGE2 induced increased EP4 receptors activation by antagonising the activation of EP4 receptors by compound 1.

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  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne l'utilisation du composé 1 pour le traitement de l'arthrite, en particulier de la polyarthrite rhumatoïde, de la spondylarthrite ankylosante, de l'arthrite psoriasique, ainsi que d'autres maladies rhumatismales à médiation immunitaire.
PCT/EP2018/072132 2017-08-22 2018-08-15 Utilisation d'un antagoniste d'ep4 pour le traitement de l'arthrite Ceased WO2019038156A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113440614A (zh) * 2020-03-26 2021-09-28 长沙晶易医药科技有限公司 一种用于治疗类风湿性关节炎的组合物及其应用
WO2022102731A1 (fr) 2020-11-13 2022-05-19 小野薬品工業株式会社 Traitement du cancer par utilisation combinée d'un antagoniste d'ep4 et d'un inhibiteur de point de contrôle immunitaire

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WO2009020588A1 (fr) 2007-08-09 2009-02-12 Merck & Co., Inc. Procédé pour fabriquer un dérivé de carboxamide de thiophène
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113440614A (zh) * 2020-03-26 2021-09-28 长沙晶易医药科技有限公司 一种用于治疗类风湿性关节炎的组合物及其应用
WO2022102731A1 (fr) 2020-11-13 2022-05-19 小野薬品工業株式会社 Traitement du cancer par utilisation combinée d'un antagoniste d'ep4 et d'un inhibiteur de point de contrôle immunitaire

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