WO2015136887A1 - Inhibiteur de croissance des cellules synoviales et méthode d'inhibition de la croissance des cellules synoviales - Google Patents

Inhibiteur de croissance des cellules synoviales et méthode d'inhibition de la croissance des cellules synoviales Download PDF

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WO2015136887A1
WO2015136887A1 PCT/JP2015/001118 JP2015001118W WO2015136887A1 WO 2015136887 A1 WO2015136887 A1 WO 2015136887A1 JP 2015001118 W JP2015001118 W JP 2015001118W WO 2015136887 A1 WO2015136887 A1 WO 2015136887A1
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rheumatoid arthritis
synovial
endoplasmic reticulum
cells
synovial cell
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PCT/JP2015/001118
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English (en)
Japanese (ja)
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越智　光夫
聡太朗 泉
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国立大学法人広島大学
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a synovial cell proliferation inhibitor and a method of inhibiting synovial cell proliferation.
  • Rheumatoid arthritis (hereinafter sometimes referred to as “RA”) is a systemic inflammatory disease whose main lesion is multiple synovial arthritis. It is common among women in their 30s and 50s, but childhood and older onset are also observed. The number of patients in Japan is about 700,000, of which about 10% are disabled. Symptoms of joint pain, swelling, redness and tenderness are observed symmetrically with systemic symptoms such as fatigue and morning stiffness. The progress of bone / joint destruction due to arthritis causes subluxation and various joint deformations as well as ligament relaxation and tendonitis.
  • the type of disease due to progression of rheumatoid arthritis is classified as type 3, and many are multi-cycle (70%), but there are also single-cycle (20%) and progressive (10%) that show remission within 2 years. .
  • various extra-articular symptoms have also been observed during the course, and poor clinical prognosis based on vasculitis is regarded as a concept of malignant rheumatoid arthritis in Japan.
  • helper T cells When antigen-presenting cells (macrophages, dendritic cells) are activated for some reason, HLA class II and antigen are presented to helper T cells, resulting in activation of helper T cells. Its activation requires a costimulatory signal (CD28 / B7), which involves adhesion molecules.
  • CD28 / B7 costimulatory signal
  • a system that differentiates helper T cells into B cells and plasma cells and produces autoantibodies such as rheumatoid factor is activated. Soluble immune complexes containing rheumatoid factors are phagocytosed by neutrophils, and prostaglandins, lysosomal enzymes, active oxygen, etc. produced from activated neutrophils cause tissue damage.
  • cytokines such as IL-1 and TNF- ⁇ are produced (“synovial inflammation” in the pathological mechanism of rheumatoid arthritis). These lead to synovial cell proliferation, osteoclast activation, fibroblast proliferation, chondrocyte damage ("synovial hyperplasia" in the pathological mechanism of rheumatoid arthritis).
  • prostaglandins and cytokines such as PGE 2 , IL-1, IL-6, IL-8, and MCP-1 are produced by the proliferation of synovial cells, and the production of proteases including collagenase and the like is enhanced along with chondrocytes. Resulting in bone destruction ("joint destruction" of the pathological mechanism of rheumatoid arthritis). These cytokines are also involved in the activation of cells involved in systemic immunity and inflammation.
  • Immunomodulators include D-penicillamine, bucillamine, lobanzarit, actarit, etc., but are not equally effective in all rheumatoid arthritis patients, and there are also serious side effects.
  • Immunosuppressants include methotrexate, mizoribine, leflunomide and the like, but these drugs sometimes have serious side effects.
  • IL-1 and TNF- ⁇ are important cytokines involved in synovitis and osteoarticular destruction of rheumatoid arthritis, and biological preparations that inhibit these cytokines are attracting attention.
  • the most effective anti-cytokine therapy is an inhibitor against TNF- ⁇ that plays a central role in inflammation of rheumatoid arthritis, such as infliximab, a chimeric anti-TNF monoclonal antibody (containing 25% mouse protein) .
  • This biologic is administered systemically and its effect is often observed from about the second week.
  • the therapeutic effects of the biologics described above may be reduced while administration is continued. This is called escape reduction.
  • side effects such as infections including tuberculosis and hypersensitivity reactions may also occur.
  • Endoplasmic reticulum stress refers to the accumulation of unfolded protein that is not folded into a normal higher-order structure in the endoplasmic reticulum, thereby causing adverse effects on the cells (stress). Excessive or persistent endoplasmic reticulum stress interferes with the normal physiological functions of the cell, so the cell is equipped with a mechanism that avoids the damage and maintains homeostasis.
  • This cellular response to endoplasmic reticulum stress is referred to as endoplasmic reticulum stress response (UPR).
  • UTR endoplasmic reticulum stress response
  • Three single-transmembrane proteins (IRE1, PERK, ATF6) present on the endoplasmic reticulum membrane sense abnormal protein accumulation as endoplasmic reticulum stress sensors and transmit signals to the cytoplasm or nucleus.
  • Patent Document 1 describes an IRE1 inhibitor compound as a drug for treating a B cell autoimmune disease, and rheumatoid arthritis as a specific example of the B cell autoimmune disease.
  • Non-Patent Document 1 describes the effect of 8-formyl-7-hydroxy-4-methylcoumarin (4 ⁇ 8C) on macrophages that differentiate bone marrow-derived undifferentiated cells into macrophages.
  • Patent Document 1 does not have an example regarding the treatment of rheumatoid arthritis using the IRE1 inhibitor compound described in the document, and the therapeutic effect of the IRE1 inhibitor compound described in the document on rheumatoid arthritis is unknown.
  • Non-Patent Document 1 merely describes the immune response of macrophages outside the joint. As described above, the pathological mechanism of rheumatoid arthritis is divided into three stages: synovial inflammation, synovial hyperplasia, and joint destruction. Needless to say, the ultimate goal of rheumatoid arthritis treatment is to suppress joint destruction.
  • the present invention has been made in view of such problems, and an object of the present invention is to provide a synovial cell proliferation inhibitor and a proliferation inhibition method that can appropriately inhibit the proliferation of synovial cells.
  • the synovial cell proliferation inhibitor according to the present invention is characterized by containing at least one compound of formula 1 or formula 2.
  • the method for inhibiting the proliferation of synovial cells according to the present invention is characterized by using a drug containing at least one compound of Formula 1 or Formula 2.
  • a synovial cell proliferation inhibitor and a proliferation inhibition method capable of appropriately suppressing the proliferation of synovial cells.
  • a therapeutic agent for rheumatoid arthritis having a sufficient therapeutic effect on rheumatoid arthritis can be obtained.
  • the synovial cell proliferation inhibitor according to the present invention is applied to the treatment of rheumatoid arthritis, it is expected to exert an early therapeutic effect, has a continuous therapeutic effect, and develops rheumatoid arthritis without systemic administration as in the past Since it can be administered to the place where it is, the effect on the whole body can be reduced and only the local area can be treated.
  • FIG. 3 is a photograph showing a tissue in which antigen-induced arthritis (AIA) has been improved by the action of STF-083010. It is a figure which shows an arthritis index. It is a figure which shows Fold induction in the case of ATF6. It is a figure which shows Fold induction in the case of PERK. It is a figure which shows Fold induction in the case of IRE1. It is a figure which shows Fold induction in the case of Edem.
  • the synovial cell proliferation inhibitor according to this embodiment contains at least one compound of Formula 1 or Formula 2.
  • the compound according to Formula 1 is STF-083010 (N-[(2-Hydroxynaphthalen-1-yl) methylidene] thiophene-2-sulfonamide).
  • the compound according to Formula 2 is 3′-Formyl-4′-hydroxy-5′-methoxybiphenyl-3-carboxamide.
  • a method for preventing and / or treating rheumatoid arthritis is characterized by using a drug containing at least one compound of Formula 1 or Formula 2.
  • treatment includes curing symptoms, improving symptoms, and suppressing progression of symptoms.
  • prevention refers to prevention or delay of the onset of symptoms.
  • a secreted protein is normally folded and a mechanism for removing / degrading the protein that has become an abnormally folded structure is required. Both of these tasks are performed in the endoplasmic reticulum, where there are regulatory mechanisms to maintain protein homeostasis.
  • the accumulation of abnormally folded proteins in the endoplasmic reticulum is called endoplasmic reticulum stress. Endoplasmic reticulum stress is caused by environmental changes inside and outside the cell. For example, normal folding of proteins is inhibited by nutrient starvation, viral infection, oxidative stress stimulation, etc. to cells, resulting in endoplasmic reticulum stress.
  • the regulatory mechanism that maintains protein homeostasis is considered to be a physiological response of cells corresponding to endoplasmic reticulum stress, and is referred to as endoplasmic reticulum stress response (UPR).
  • the endoplasmic reticulum stress response mechanism is composed of three reactions: (i) translational repression, (ii) transcriptional induction of endoplasmic reticulum molecular chaperones, and (iii) abnormal protein degradation by endoplasmic reticulum-related degradation (ERAD) (Fig. 1).
  • ESD endoplasmic reticulum-related degradation
  • IRE1 is an endoplasmic reticulum transmembrane kinase and has an RNase domain at the C-terminus on the cytoplasm side.
  • IRE1 detects an abnormal protein, its steric structure changes due to autophosphorylation, and as a result, the C-terminal RNase domain is activated and splices the substrate XBP1 (X-box binding protein 1) mRNA.
  • XBP1 X-box binding protein 1
  • Molecules that are transcriptionally induced by XBP1 that have transcriptional activity are an endoplasmic reticulum chaperone group and a series of genes related to ERAD. Since XBP1 has a short intron, it has no translation inhibitory action, and the precursor XBP1 mRNA is also translated. Thus, the IRE1-XBP1 pathway functions to eliminate and decompose abnormal proteins from the endoplasmic reticulum and restore homeostasis of the endoplasmic reticulum.
  • the IRE1 inhibitor is an agent that inhibits the function of IRE1, and specifically, an agent that has a function of inhibiting the flow of the IRE1-XBP1-EDEM pathway.
  • IRE1 is the main therapeutic target in rheumatoid arthritis among endoplasmic reticulum stress sensors.
  • Rheumatoid arthritis causes chondrocyte damage by proliferation of synovial cells, but the present inventor inhibits activation of the XBP1 gene by suppressing ER1, which is an endoplasmic reticulum stress sensor (endoplasmic reticulum stress response).
  • ER1 is an endoplasmic reticulum stress sensor (endoplasmic reticulum stress response).
  • FIG. 2 shows the pathological mechanism of rheumatoid arthritis.
  • Rheumatoid arthritis is considered a multifactorial disease and develops on the basis of genetic background, infection and tobacco. When it develops, it begins to develop an autoimmune response to some antigen of its own.
  • Antigen presenting cells recognize self as non-self and activate B cells and T cells.
  • B cells produce antibodies, and T cells activate macrophages (M ⁇ ).
  • M ⁇ macrophages
  • Activated M ⁇ produces various inflammatory cytokines such as tumor necrosis factor (TNF) ⁇ and interleukin (IL) -1,6 (upstream response).
  • TNF ⁇ and IL-1 not only activate macrophages themselves, but also activate and proliferate the fibroblasts that form the synovium.
  • Proliferated synovial fibroblasts are affected by the release of large amounts of IL-6 and other cytokines, as well as the production of proteolytic enzymes that destroy joint tissue, forming a villi-like tissue called pannus in the joint Destroy bone and cartilage of joints (downstream response).
  • the contents reported in The EMBO Journal which is a non-patent document 1, reports the action of IRE1 in M ⁇ when differentiating undifferentiated cells derived from bone marrow into M ⁇ and administering 4 ⁇ 8C. That is, it shows the immune response of M ⁇ outside the joint (response upstream).
  • the present invention uses synovial cells isolated from knee synovial tissue of rheumatoid arthritis patients, and shows the function of IRE1 in synoviocytes when a compound according to Formula 1 or Formula 2 is administered. Yes (downstream response).
  • the synovial proliferation by inflammatory cytokines in the joint is observed, and the apoptosis of synoviocytes (suppression of synovitis) is defined when the compound according to Formula 1 or Formula 2 is administered in the joint. is doing.
  • the activity may increase again without changing the treatment method, and this phenomenon is called escape phenomenon.
  • escape phenomenon When the escape phenomenon appears, the activity of rheumatoid arthritis increases 2-3 years after the start of administration.
  • the compound according to Formula 1 or Formula 2 is administered intra-articularly to increase the apoptosis of synovial cells and create a situation in which there are no synovial cells for causing an immune response. As shown in the embodiment, such an escape phenomenon can be avoided.
  • the preparation form of the synovial cell proliferation inhibitor according to this embodiment is not particularly limited, but is preferably an injection preparation. By making the preparation for injection, it can be easily applied to small joints such as fingers.
  • Injectable preparations are prepared, for example, in the form of solutions, emulsions or suspensions, and are made isotonic with blood.
  • Formulations in the form of liquids, emulsions or suspensions are prepared using, for example, an aqueous medium, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester .
  • the aqueous medium include water or a medium containing water.
  • sterilized water is used.
  • the medium containing water include physiological saline, PBS (phosphate buffered physiological saline), lactic acid-containing Ringer's solution, and the like.
  • the content allowed in an injectable preparation is not particularly limited as long as no adverse effects such as side effects occur, but the dosage is, for example, 0.01 to 10 mg / mL, preferably 0.05 to 5 mg / mL.
  • methotrexate (MTX) a prominent drug for rheumatoid arthritis, is orally administered at 6 mg per week in principle. However, its usage is divided into 2-4 times per week and is divided into 1-2 at 12-hour intervals. It is administered over a period of days.
  • the present invention creates a situation in which synoviocytes for causing an immune reaction do not exist, the sustainability of the medicinal effect can be greatly improved as compared with the conventional method, and the usage is not particularly limited. Can be administered at intervals of, for example, 6 to 18 weeks.
  • additives usually used in the art can be appropriately used.
  • examples of the additive include isotonic agents, stabilizers, buffers, preservatives, chelating agents, antioxidants, and solubilizing agents.
  • Examples of the isotonic agent include glucose, sorbitol, sodium chloride, glycerin and the like.
  • Examples of the stabilizer include sodium sulfite.
  • Examples of the buffer include a borate buffer and a phosphate buffer.
  • Examples of the preservative include p-hydroxybenzoate ester, benzyl alcohol, chlorocresol and the like.
  • Examples of chelating agents include sodium edetate and sodium citrate.
  • Examples of the antioxidant include sodium sulfite and sodium hydrogen sulfite.
  • Examples of the solubilizer include dextran, polyvinyl pyrrolidone and the like.
  • the preparation for injection may contain a pH adjuster.
  • the pH adjuster may be an acid or a base.
  • examples of the acids include ascorbic acid and hydrochloric acid.
  • Examples of the base include potassium hydroxide and calcium hydroxide.
  • Example 1 shows the results of an in vivo therapeutic effect test for rheumatoid arthritis using STF-083010, a kind of IRE1 inhibitor.
  • mice were given the primary sensitization by subcutaneous administration of 10 ⁇ g / body of methylated bovine serum albumin (mBSA) as the antigen, and 10 days later, 20 ⁇ g / joint of mBSA was injected into the knee joint for secondary sensitization.
  • Rheumatoid arthritis (antigen-induced arthritis: AIA) model mice were created by inducing arthritis. This method is widely accepted worldwide.
  • FIG. 3 a tissue image in which synovitis was actively occurring was confirmed on the knee of the mouse on the 17th day. However, when STF-083010 was administered into the mouse knee joint on the 11th day, as shown in FIG.
  • FIG. 5 shows the arthritic index.
  • mBSA 20 ⁇ g / joint was injected into the knee joint 10 days later, followed by secondary sensitization, and the arthritic index on the 17th day.
  • mBSA 20 ⁇ g / joint was injected into the knee joint for secondary sensitization, and on the 11th day, the next day, STF-083010 was injected into the mouse knee joint at 10 ⁇ M.
  • STF-083010 was injected into the mouse knee joint at 10 ⁇ M.
  • the arthritis index is scored using a knee section of a rheumatoid arthritis model mouse, and is classified into five types: synovitis, appearance of inflammatory cells in the joint, inflammation of soft tissue, cartilage damage, and bone destruction. For items, 0 to 3 points are evaluated as 3 points, with a total of 15 points being the maximum. As shown in FIG. 5, it was shown that the arthritis index was dramatically reduced when STF-083010 was used at 10 ⁇ M and at 100 ⁇ M. It should be noted that the concentration of these IRE1 inhibitors may be administered while further reducing the side effects.
  • Example 2 shows the results of experiments in which IRE1 is the main therapeutic target in rheumatoid arthritis among ER stress sensors IRE1, PERK, and ATF6.
  • synovial cells were separated from the synovial tissue collected from the knee joints of rheumatic patients who had given consent, cultured on a petri dish, and stimulated. The cells were immersed in the respective culture solutions for 0 hours, 3 hours, 6 hours, and 12 hours, and then the cells were collected, and the expression of mRNA in ATF6, PERK, and IRE1 cells was measured by PCR.
  • FIG. 6 shows the case of ATF6
  • FIG. 7 shows the case of PERK
  • FIG. 8 shows the case of IRE1.
  • DMSO is a control group showing that the solution itself is not toxic.
  • + IL-1 + TNF- ⁇ indicates that IL-1 and TNF- ⁇ are added to the cell culture medium, and the cells derived from rheumatic patients create an inflammatory situation closer to that of the living body.
  • IRE1 unlike in the case of ATF6 and PERK, the inflammation of rheumatism occurred, and only IRE1 showed a movement different from the control.
  • IRE1 may be a major regulator of the inflammatory response when synovitis occurs in synovial cells of rheumatoid arthritis patients.
  • STF STF to IL-1 and TNF- ⁇ indicates that the expression of IRE1 is particularly reduced, which is considered to indicate evidence of selective inhibition of IRE1.
  • Example 3 In Example 3, in the case of EDEM and ERdj5, the expression of each mRNA was measured using the same method. It is said that EDEM downstream of IRE1 directly controls the ERAD system in the endoplasmic reticulum. As shown in FIG. 9, it was shown that the expression was considerably decreased after 12 hours by adding STF-083010 so that EDEM also synchronized with IRE1.
  • ERdj5 is an oxidoreductase endogenous to the endoplasmic reticulum identified as a protein that binds to EDEM1, and promotes endoplasmic reticulum-related degradation of abnormal proteins by reducing disulfide bonds formed between incorrect cysteine residues . As shown in FIG. 10, ERdj5 did not show decreased expression even when STF-083010 was added.
  • Example 4 TUNEL method positive apoptotic cells were measured.
  • the TUNEL method is a method for detecting fragmented DNA generated in the process of apoptosis (programmed cell death) by the TUNEL (TdT-mediated dUTP nick end labeling) method. After the fragmented DNA was labeled with biotin-labeled nucleotides, it was stained by reacting with HRP-labeled streptavidin. As shown in FIG. 11, by adding STF-083010, after 12 hours, it was shown that 50% or more of the synovial cells derived from rheumatic patients in the petri dish had undergone apoptosis.
  • Example 5 In Example 5, the usefulness of STF-083010 in recurrent AIA model mice was confirmed. No animal model suitable for recurrent AIA model mice has been reported in the past, but recurrent AIA model mice were prepared as follows. That is, on the 1st day, mBSA 10 ⁇ g / body as the antigen was subcutaneously administered to the mouse on the dorsal caudal side to give the primary sensitization, and 10 days later, mBSA 20 ⁇ g / joint was injected into the knee joint and the secondary sensitization Caused arthritis. On the 11th day, arthritis was once suppressed using STF-083010. In the control model, DMSO was administered into the joint instead of STF-083010.
  • FIG. 12 (A) is an immunostaining diagram showing the state of arthritis in the knee joint of the recurrent AIA model
  • FIG. 12 (B) is a partially enlarged view of (A).
  • FIG. 13 is a diagram showing an arthritic index of a recurrent AIA model. This showed that the first administration of STF-083010 may not have synovial cells for raising an immune response against mBSA.

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Abstract

La présente invention se rapporte à un inhibiteur de croissance des cellules synoviales qui peut, d'une manière appropriée, inhiber la croissance des cellules synoviales, et qui est caractérisé par la formule 1. La réponse au stress du réticulum endoplasmique est inhibée, et le stress du réticulum endoplasmique induit l'apoptose des cellules synoviales, ce qui supprime la synovite. La polyarthrite rhumatoïde détruit le cartilage des articulations, et donc les articulations, au moyen d'enzymes protéolytiques et d'une cytokine sécrétée à cause de la croissance anormale des cellules synoviales. En inhibant l'IRE1, la transcription et l'activation du gène XBP1 sont inhibées (la réponse au stress du réticulum endoplasmique est inhibée), et en supprimant le système ERAD, l'apoptose est induite dans les cellules synoviales, ce qui supprime la croissance des cellules synoviales.
PCT/JP2015/001118 2014-03-10 2015-03-03 Inhibiteur de croissance des cellules synoviales et méthode d'inhibition de la croissance des cellules synoviales WO2015136887A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010529147A (ja) * 2007-06-08 2010-08-26 マンカインド コーポレ−ション ＩＲＥ−１αインヒビター
WO2012064774A1 (fr) * 2010-11-10 2012-05-18 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteur spécifique de l'endonucléase ire1 alpha ayant une activité cytotoxique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010529147A (ja) * 2007-06-08 2010-08-26 マンカインド コーポレ−ション ＩＲＥ−１αインヒビター
WO2012064774A1 (fr) * 2010-11-10 2012-05-18 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteur spécifique de l'endonucléase ire1 alpha ayant une activité cytotoxique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
QIU Q ET AL.: "Toll-like receptor-mediated IRE1alpha activation as a therapeutic target for inflammatory arthritis.", EMBO J., vol. 32, no. 18, 2013, pages 2477 - 2490, XP055223483 *

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