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WO2018162562A1 - Utilisation d'un antagoniste d'ep4 pour le traitement de la douleur inflammatoire - Google Patents

Utilisation d'un antagoniste d'ep4 pour le traitement de la douleur inflammatoire Download PDF

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Publication number
WO2018162562A1
WO2018162562A1 PCT/EP2018/055615 EP2018055615W WO2018162562A1 WO 2018162562 A1 WO2018162562 A1 WO 2018162562A1 EP 2018055615 W EP2018055615 W EP 2018055615W WO 2018162562 A1 WO2018162562 A1 WO 2018162562A1
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Prior art keywords
inhibitors
compound
pain
treatment
inflammatory pain
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Ceased
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PCT/EP2018/055615
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English (en)
Inventor
Jens Nagel
Stefan BÄURLE
Maik Obendorf
Markus Koch
Gernot Langer
Anne-Marie GODINHO-COELHO
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Definitions

  • the present invention relates to the use of an EP4 antagonist for the treatment and/or prophylaxis of inflammatory pain and/or other pathological conditions related to increased activation of EP4 receptors by prostaglandin E2 (PGE2).
  • PGE2 prostaglandin E2
  • inflammatory pain is one form of nociceptive pain which is typically accompanied by an immune response and mediated by pro-inflammatory molecules which are released by tissue due to a trigger which endangers or destroys cell integrity or signals endangered cell integrity.
  • activated nociceptors peripheral nerve endings of the pain pathway
  • non-neural cells that reside within or infiltrate into the injured/endangered area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts).
  • these factors represent a wide array of signaling molecules, including neurotransmitters, peptides (substance P, CGRP, bradykinin), eicosinoids and related lipids like prostaglandins which include the endogenous activators of the EP4 receptor, thromboxanes, leukotrienes, endocannabinoids, neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons.
  • Nociceptors express one or more cell-surface receptors capable of recognizing and responding to each of these pro- inflammatory or pro-algesic agents.
  • Inflammatory pain of varied origins is associated but not limited to osteoarthritis, rheumatoid arthritis, rheumatic disease, tenosynovitis, gout, ankylosing spondylitis, endometriosis, injuries, various skin diseases and bursitis.
  • NSAID nonsteroidal anti-inflammatory drugs
  • PGE2 endogenously formed prostaglandin E2
  • 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 cAMP.
  • GPCR membrane- bound G-protein coupled receptors
  • the expression of the receptor was detected on peripheral nerve endings of nociceptors, on macrophages and neutrophils. For these cell types, great importance was demonstrated in connection with inflammatory pain. It is assumed that the local inflammation of the endometriotic lesions makes a significant contribution to the genesis of the pain symptoms observed (Stratton & Berkley 2010; Giudice 2010).
  • EP4 antagonists of different structural classes have been described, Thus in WO2005/0121508, WO2005102389 and WO2005/105733 (Pfizer), for example, N-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-A/-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 inflammatory pain and/or other pathological conditions related to increased activation of EP4 receptors by prostaglandin E2 (PGE2).
  • PGE2 prostaglandin E2
  • the compound showed after p.o. administration robust effects in in vivo studies in mice and rats.
  • the compound attenuated inflammatory pain and edema formation in various settings.
  • the compound can be employed for long term treatment (fig. 5).
  • the suppression of PGE2 induced proliferation of uterine tissue was shown in vitro and in vivo in mice. Therefore the use of compound 1 for the treatment of inflammatory pain and/or other pathological conditions related to 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 charactistics of compound 1 .
  • Experiments were performed to show that the binding is antagonistic (Part a), agonistic (part B) or inverse agonistic (Part C).
  • Part a antagonistic
  • Part B agonistic
  • Part C inverse agonistic
  • the results show that compound 1 is a highly potent, competitive human EP4 receptor antagonist with inverse agonist activity.
  • Figure 2 Effect of Compound 1 on CFA induced pain.
  • Compound 1 was given in increasing concentrations ranging from 0.2 to 25 mg/kg. The figure clearly shows that compound 1 reduced inflammatory pain significantly and dose-dependently ( * p ⁇ 0.05, ** p ⁇ 0.01 , *** p ⁇ 0.005, **** p ⁇ 0.001 , ANOVA followed by post hoc test (Dunnett) vs vehicle).
  • Compound 1 was given in following concentrations: 1 mg/kg, 5 mg/kg and 25 mg/kg.
  • Figure 4 shows that compound 1 significantly reduced PGE2 induced pain ( * p ⁇ 0.01 vs vehicle, analysed by 1 -way ANOVA followed by Dunnett ' s post hoc test).
  • Figure 5 represents the effect of compound 1 on cell proliferation.
  • Compound 1 100 nM was given with (crossed bar) or without (vertical hatched bar) 10 nM PGE2, PGE2 was also given alone (horizontal hatched bar).
  • PGE2 was also given alone (horizontal hatched bar).
  • the total cell number did not increase when compared with the group which contained PGE2 alone.
  • Compound 1 together with PGE2 also did not affect the total cell number.
  • Figure 6 demonstrates that stabilized PGE2, applied directly in the cavity of the uterus, induced proliferation in uterine tissue in aenesthetized mice.
  • Compound 1 was given in concentrations ranging from 0.2 to 25 mg/kg; compound 1 dose-dependently suppressed PGE2-induced cell number increase in uterine tissue ( * p ⁇ 0.05 and ** p ⁇ 0.01 compared to 2 mg/kg dm-PGE2 group, 3 outliers following Grubbs test removed, analysed by 1 -way ANOVA followed by Dunnett's post hoc test).
  • Figure 7 Effect of compound 1 in endomet iosis dyspareunia model (rat, vaginal distension
  • Figure 7 shows the effect of compound 1 in an endometriosis dyspareunia model. Open bars represent the vehicle group, hatched bars represent the compound group, and crossed bars show the effect of ibuprofen.
  • Compound 1 decreased vaginal hyperalgesia in a rat endometriosis model. + stands for: cumulative number of contraction per 0.1 ml distension and ++ for: different vehicle, these were excluded from statistical analysis
  • the present invention is based on the discovery that compound 1 is highly potent in the treatment of inflammatory pain and/or other pathological conditions related to increased activation of EP4 receptors by prostaglandin E2 (PGE2). Therefore subject matter of the present invention is directed to the use of compound 1 for treatment of inflammatory pain and/or other pathological conditions related to increased activation of EP4 receptors by prostaglandin E2 (PGE2).
  • Inflammatory pain inflammatory pain is selected from a group comprising but not limited to ankylosing spondylitis, or pain associated with endometriosis, post operative pain, pain related to skin burn injuries and osteoarthritis.
  • 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 endometriosis.
  • Suitable combination active substances that may be mentioned by way of example and preferably are: selective oestrogen receptor modulators (SERMs), oestrogen receptor (ER) antagonists, aromatase inhibitors, 17 ⁇ -HSD1 inhibitors, steroid sulphatase (STS) inhibitors, GnRH agonists and antagonists, kisspeptin receptor (KISSR) antagonists, selective androgen receptor modulators (SAR s), androgens, 5 ⁇ -reductase inhibitors, selective progesterone receptor modulators (SPRMs), gestagens, antigestagens, oral contraceptives, inhibitors of mitogen activated protein (MAP) kinase and inhibitors of MAP kinases (Mkk3/6, Mek1/2, Erk1/2), inhibitor
  • Compound 1 can be employed for the treatment of inflammatory pain, both after oral as well as parenteral administration.
  • Inflammatory pain includes forms of acute and chronic pain, including chronic pelvic pain, endometriosis associated pain, as well as pain associated with angina, or pain of varied origins (including but not limited to pain associated with osteoarthritis, rheumatoid arthritis, rheumatic disease, tenosynovitis, gout, bursitis, post operative pain, pain related to skin burn injuries, and ankylosing spondylitis. Therefore subject matter of the present invention is also the use of compound 1 for the treatment of inflammatory pain, whereby the inflammatory pain is selected from a group comprising but not limited to ankylosing spondylitis, or pain associated with endometriosis, post operative pain, pain related to skin burn injuries and osteoarthritis
  • 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, between 1 -500 mg/day, preferably between 5 and 30 mg/day, where the dose can be given as an individual dose to be administered once or subdivided into 2 or more daily doses.
  • 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.
  • administration forms functioning according to the prior art, 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, are 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.
  • 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 gelatin
  • Parenteral administration can take place circumventing an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinaliy or intralumbarly) or with inclusion of an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • an absorption step e.g. intravenously, intraarterially, intracardially, intraspinaliy 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, vaginal capsules and suppositories, tampons, intrauterine pessaries, 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, intrauterine spirals, vaginal rings or stents are suitable.
  • pharmaceutical forms for inhalation inter alia powder inhalers, nebulizers
  • nose drops solutions or sprays
  • 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 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/dayNevertheless, 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. Thus, in some cases it can be adequate to manage with less than the aforementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the administration of relatively large amounts, it can be advisable to divide these into a number of individual doses over the course of the day.
  • 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 an Eu-cryptate labelled anti-CAMP antibody.
  • Maximum signal obtained via fluorescence resonance energy transfer; FRET
  • FRET fluorescence resonance energy transfer
  • An appropriate plate reader (RubyStar, PheraStar, ViewLux) is used to induce and measure FRET emissions at 620 and 665nm following excitation at 337 nm. Any signal-decrease shows activation of the GPCR (i.e. change in well-Ratio; defined as 665nm / 620nm * 10000). Antagonists result in signal increase.
  • 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: Poiystyroi; 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 (5ml_) according to suppliers manual.
  • Step 2 Further 1 :39 dilution with Conjugate & Lysis Buffer.
  • Conjugate & Lysisbuffer prepared according to cAMP kit protocol (Cisbio).
  • CFA Complete Freund's Adjuvant
  • Endpoint 1 Dynamic weight bearing (DWB)
  • the automated DWB device (Bioseb, Boulogne, France) consists of a Plexiglas enclosure (22x22x30cm), a floor sensor composed of captors in order to detect pressure variation and a camera placed above the enclosure in order to validate the animal position during analysis (Robinson et al., 2012; Tetreault et al., 201 1 ).
  • the rats were able to move freely in the enclosure during 5 min while the acquisition data were transmitted to a computer.
  • the animals were not acclimated to the enclosure before the test.
  • Endpoint 2 Paw weight analysis (edema)
  • the paw was removed from the dead animal at the ankle joint and weight of the paw was noted.
  • Figure 4 shows that PGE2 induced pain is mediated by EP4 receptors.
  • Compound 1 significantly reduced PGE2 induced pain dose dependendly.
  • Cells (Cell culture: EM42 cells (Desai et al., 1994, Fert. Steril. 61 : 760) were cultivated one passage before experiment in test media (DMEM w/o phenolred, 1 % Pen/strep, 1 % L- glutamine plus indicated concentration of FCS [e.g. :1 %])
  • Indicated number of cells (e.g. 1000) was plated in wells of 96well plates (Perkin Elmer #6005688). Substances were added as indicated in tetraplicates, inhibitors were added first. PGE2 was given twice daily. For incubation without PGE2 the same amount of media was added twice daily. Incubation of MTPs for 4 days at 37°C and 5% CO? was followed by a CellTiter Glo measurement at day 4.
  • Preparation of cell number calibration curve from cells in test media Cells were counted for calibration and plated in duplicates in rows 1 and 2 and incubated for two hours. Celltiter Glo measurement was performed as described by vendor (Promega #G7571 ). Briefly, MTPs were adjusted to room temperature for 30 minutes. 100 ⁇ ! celltiter reagent was added, followed by mixing and incubation for 10 minutes. The luminescence was measured of with POLARstar (bmg). Measurements of relative light units (RLU) and calculation of cell number equivalent was performed by employing linear part of calibration curve.
  • RLU relative light units
  • EXAMPLE 6 Effect of compound 1 in endometriosis dyspareunia model (rat, vaginal distension
  • VMR viscero motor response
  • VD vaginal distension
  • Compound 1 decreased vaginal hyperalgesia versus vehicle-treated animals. The effect maintained in the treatment free period of week 6. Therefore compound 1 is suitable for long term treatment of the aforementioned diseases. This might point to a disease modyfing component induced by the EP4 receptor antagonism exceeding pure analgesic activity. Interestingly, daily dosed compound 1 showed a more pronounced effect than acute treatment with one analgesic dose of ibuprofenoilected to measure the VMR related to the distension.

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Abstract

La présente invention concerne l'utilisation du composé 1 pour le traitement de la douleur inflammatoire.
PCT/EP2018/055615 2017-03-10 2018-03-07 Utilisation d'un antagoniste d'ep4 pour le traitement de la douleur inflammatoire Ceased WO2018162562A1 (fr)

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EP17160290.7 2017-03-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019038156A1 (fr) * 2017-08-22 2019-02-28 Bayer Pharma Aktiengesellschaft Utilisation d'un antagoniste d'ep4 pour le traitement de l'arthrite

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WO2003086371A2 (fr) 2002-04-12 2003-10-23 Pfizer Japan Inc. Utilisation de ligands du recepteur ep4 dans le traitement de maladies impliquant il-6
WO2004067524A1 (fr) 2003-01-29 2004-08-12 Pharmagene Laboratories Limited Antagonistes aux recepteurs ep4
WO2005102389A2 (fr) 2004-04-20 2005-11-03 Pfizer Products Inc. Combinaisons contenant des ligands de alpha-2-delta
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WO2005121508A2 (fr) 2004-06-02 2005-12-22 Sunpower, Inc. Procede et appareil permettant de fabriquer un echangeur thermique
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WO2008017164A1 (fr) 2006-08-11 2008-02-14 Merck Frosst Canada Ltd. Dérivés de thiophènecarboxamide en tant que ligands du récepteur ep4
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WO2014086739A1 (fr) 2012-12-06 2014-06-12 Bayer Pharma Aktiengesellschaft Nouveaux dérivés du benzimidazole comme antagonistes ep4
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WO2002032422A2 (fr) 2000-10-19 2002-04-25 Pfizer Pharmaceuticals Inc. Inhibiteurs du recepteur ep4 destines au traitement de la polyarthrite rhumatoide
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WO2014086739A1 (fr) 2012-12-06 2014-06-12 Bayer Pharma Aktiengesellschaft Nouveaux dérivés du benzimidazole comme antagonistes ep4
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CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 122060-05-3

Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2019038156A1 (fr) * 2017-08-22 2019-02-28 Bayer Pharma Aktiengesellschaft Utilisation d'un antagoniste d'ep4 pour le traitement de l'arthrite

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