JP2006335666A - Prevention of joint damage - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmacological composition and a method for treating and preventing joint damages in a subject suffering from joint or musculoskeletal disorder or reducing its risk. <P>SOLUTION: The pharmacological composition comprises histone deacetylase (HDAC) inhibitor, its pharmacologically acceptable salt and a pharmacologically acceptable carrier. A hydroxamic acid derivative, a short-chain fatty acid, a cyclic tetrapeptide, a benzamide derivative or an electrophilic ketone derivative may be cited as the HDAC inhibitor. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

BACKGROUND The present invention relates to histone deacetylases (in order to treat, prevent, or reduce the risk of joint damage in subjects suffering from joint or musculoskeletal diseases by inhibiting cartilage and bone degradation and resorption in the joints. HDAC) inhibitors, or with other drugs.

  Joint damage usually occurs with spondyloarthritis, rheumatoid arthritis, degenerative joint disease, gout, infection, cancer, or trauma.

  Spondyloarthropathies are from undifferentiated spondyloarthropathy, ankylosing spondylitis, juvenile ankylosing spondylitis, reactive arthritis, Reiter's syndrome, psoriatic arthritis, and spondyloarthropathy associated with Crohn's disease and ulcerative colitis It is a group of diseases. Specific features of spondyloarthritis include asymmetric arthritis, muscle attachment inflammation, genital and skin lesions, eye and intestinal inflammation, association with previous or current infectious disorders, and human leukocyte antigens ( HLA) Strong association with B27. Peripheral arthritis in spondyloarthropathy develops suddenly and occurs mainly in the lower limbs, especially the knees, ankles, and lower parts of the ankles. This is typically asymmetric and often only 1-3 joints are affected. Spondyloarthropathy is diagnosed by sausage fingers (acuitis), sacroiliac arthritis, and vertebral tendon attachment. The true cause of spondyloarthropathy is not yet known. Another destructive arthropathy that needs to be distinguished from spondyloarthropathy is rheumatoid arthritis, an autoimmune disease. Symmetric polyarthritis of the small joints is a hallmark of rheumatoid arthritis. Although the etiology of spondyloarthropathy is different from that of rheumatoid arthritis, the major pathology of affected joints is commonly the inflammation of synovial and extra synovial structures such as tendons and ligaments, inflammatory cell infiltration around joint soft tissue, It consists of production of pro-inflammatory mediators and enzymes from macrophages, monocytes, and fibroblasts, synoviocyte proliferation, and cartilage and bone degradation and resorption, all contributing to the destruction of joint structures. Joint damage occurs at the site of attachment of the joint capsule, ligament, or tendon. This place is very vascular and is prone to bacterial invasion and antigen deposition.

  To date, all currently available treatments have been aimed at suppressing joint inflammation and abrupt worsening of pain, but only suppressing inflammation or immune response can lead to cartilage and bone degradation and joint damage. Insufficient to stop the long-term process of absorption (Lee, DM., Et al., Lancet 358: 903-911, 2001). The natural history of spondyloarthritis and rheumatoid arthritis is one of lifelong relapses and remissions, leading to death, mostly gastrointestinal bleeding associated with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), and steroids Due to medical effects such as infection or hepato-nephrotoxicity associated with long-term use of immunosuppressants, and other disease modifying anti-rheumatic drugs (DMARDs). Tumor necrosis factor-α (TNF-α), a major pro-inflammatory cytokine, is treated in several ways by clinical trials that neutralize either antibodies to TNF-α or soluble TNF-α receptors Anti-inflammatory effects have been obtained, but the main concerns are that the treatment must be continued, that the duration of efficacy may be reduced by repeated administration, and that discontinuation increases disease activity Long-term application increases the chance of infection, and the joint damage process does not stop (Moreland, LW., Et al., N. Engl. J. Med. 337: 41- 147, 1997). Thus, there is an urgent need for effective therapies to prevent joint damage and maintain a functional state.

Overview The present invention surprisingly demonstrates that administration of histone deacetylase (HDAC) inhibitors is effective in preventing joint damage by inhibiting cartilage and bone degradation and resorption. It was.

  Compositions and methods are provided for treating, preventing, or reducing the risk of joint damage in a subject suffering from a joint or musculoskeletal disorder. This method involves subjecting a subject with a therapeutically effective amount of an HDAC inhibitor or a pharmaceutically acceptable salt thereof, or other agent, together with a pharmaceutically acceptable carrier, and cartilage and bone degradation and resorption in a joint. Administering to inhibit.

  The compounds of the invention are administered orally, intra-articularly, intraperitoneally, intrathecally, intraarterial, intranasal, intraparenchymal, subcutaneous, intramuscular, intravenous, intradermal, intrarectal, and topically. be able to. Dosage is based on the effective concentration observed in in vitro and in vivo studies. Various useful utilities of the compounds of the present invention are concomitantly, sequentially or as second HDAC inhibitors, organic bisphosphonates, chemotherapeutic agents, radiopharmaceuticals, TNF-α antagonists, non-steroidal anti-inflammatory drugs, steroids , Antioxidant, angiogenesis inhibitor, matrix metalloproteinase inhibitor, vitamin, selective estrogen receptor modulator (SERM), estrogen-progestin, androgen, calcitonin, antibiotics, cathepsin K inhibitor, osteoclast proton ATPase Inhibitors, inhibitors of HMG-CoA reductase, statins, integrin receptor antagonists, osteoblast anabolic agents, and selective serotonin reuptake inhibitors, or pharmaceutically acceptable salts or mixtures thereof This is further illustrated by the discovery that they may be administered in combination.

  The invention will be more fully understood and further features will become apparent when reference is made to the following description of the invention and the accompanying drawings.

DETAILED DESCRIPTION The present invention preferably comprises rheumatoid arthritis, spondyloarthropathy (particularly undifferentiated spondyloarthritis, ankylosing spondylitis, juvenile ankylosing spondylitis, reactive arthritis, Reiter syndrome, psoriatic arthropathy, and clones Disease and spondyloarthropathy associated with ulcerative colitis), or bone loss, fracture, osteonecrosis, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal Disease, tooth loss, osteolysis around the prosthesis, degenerative joint disease, gouty arthritis, septic arthritis, osteogenesis imperfecta, bone cancer, multiple myeloma, malignant hypercalcemia, metastatic bone disease, and Used to treat, prevent, or reduce the risk of joint damage in subjects suffering from other destructive joint or musculoskeletal diseases such as neoplastic concomitant syndrome. Osteoporosis or osteopenia is immobilization, bone malformation, cachexia, anorexia nervosa, exercise-induced amenorrhea, chemotherapy or radiation therapy-induced amenorrhea, androgen deprivation therapy, Turner syndrome, cyst For fibrosis, diabetes, hyperthyroidism, hyperparathyroidism, Cushing syndrome, glucocorticoid excess, acute lymphoblastic leukemia, Klinefelter and Kalman syndrome, alcohol abuse, smoking, connective tissue disease, or osteoarthritis Then it happens secondarily.

  Joint damage occurs by degradation and resorption in the cartilage and bone of the joint. Bone resorption and addition are controlled and balanced by two different cell types, osteoclasts and osteoblasts, respectively. These cells are more closely related to cell contacts, cytokines, growth factors, and hormones. Interleukin (IL) -6 and NF-κB Ligand Activator Receptor of NF-κB Ligand (RANK-L) are the main sources of osteoblast / osteoclast communication Has been identified as a novel cytokine. RANK-L is expressed on stromal cells / osteoblasts and interacts with the receptor RANK present on osteoclast precursors and mature osteoclasts to induce their differentiation and / or activation (Chambers, TJ., Et al., J. Pathol. 192: 4-13, 2000). Disruption of the functional balance of IL-6 / RANK-L / RANK / NF-κB results in osteolysis (degradation) and resorption within the bone. For example, the pathogenesis mechanism of joint damage is from inflammation, immune response, infection or neoplasia to osteoclasts by overproduction of IL-6 by osteoblasts, macrophages, lymphocytes, fibroblasts, or cancer cells Is activated to increase bone resorption and release of matrix-related cytokines such as IL-1β and TNF-α as well as growth factors such as TGF-β and enzymes such as matrix metalloproteinases (MMPs) for cartilage and bone Can be started by decomposing. On the other hand, these cytokines and growth factors also increase IL-6 production via a positive feedback loop. The malignant cycle then begins to amplify signals that degrade and absorb cartilage and bone, resulting in joint damage. However, in clinical trials, either blocking cytokine activity by TNF-α antagonists and enzyme activity by MMP inhibitors or suppression of inflammatory responses by NSAID or steroids and immune responses by DMARDs alleviated joint inflammation, It has not been successful in stopping the destruction process. One possible reason for this is that if the mesenchymal and fibroblast-like synoviocytes change in response to the inflammatory cytokine environment, become locally invasive, and are not suppressed, It is thought that cartilage and bone can be directly degraded and re-absorbed indirectly via the IL-6 / RANK-L / RANK / NF-κB pathway (Muller-Ladner, U., et al , Am. J. Pathol. 149: 1607-1615, 1996).

  Drugs that have been used in the past to treat destructive joint diseases such as spondyloarthropathy and rheumatoid arthritis are based on symptomatic anti-inflammatory or disease modifying therapies. The mainstream drug for symptomatic treatment is intra-articular injection of NSAIDs, systemic steroids, or glucocorticosteroids. DMARDs contain drugs that reduce joint inflammation by affecting the body's immune response. Examples of DMARDs include methotrexate, azathioprine, gold salts, cyclophosphamide, and sulfasalazine. All these treatments unfortunately cause serious side effects and are not effective at all. For example, glucocorticoid administration is generally performed against local inflammation, that is, used directly to treat inflammatory cells present in the joint inflammation area. Administration of high doses of steroids or DMARDs causes severe side effects and infections in the body, including effects on the skeleton and muscles. TNF-α antagonists may be anti-inflammatory in some patients with spondyloarthritis and rheumatoid arthritis, but cannot prevent the joint destruction process. In addition, the development of active tuberculosis and demyelinating central nervous system disease has been recognized as a serious adverse effect of anti-TNF-α therapy (Baeten, D., et al., Ann. Rheum. Dis. 62: 829, 2003).

  For this reason, the use of HDAC inhibitors or in combination with other drugs to prevent joint damage in joint or musculoskeletal diseases has never been suggested or disclosed. The present invention demonstrates that HDAC inhibitors, or in combination with other drugs, can treat, prevent, or reduce the risk of joint damage by inhibiting cartilage and bone degradation and resorption in joints. is there.

  HDAC inhibitors are a class of compounds with multiple gene regulatory capabilities that increase histone acetylation and regulate the expression of specific gene sets, and regulate the chromatin structure and target gene accessibility to transcription to control disease. Can be treated (Marks, PA., Et al., J. Natl. Cancer Inst., 92: 1210-6, 2000). HDAC inhibitors selectively affect gene expression and alter the expression of only about 2% of genes expressed in cultured tumor cells. Over-acetylation of histones up-regulates cell cycle inhibitors (p21Cip1, p27Kip1, and p16INK4), down-regulates oncogenes (Myc and Bcl-2), and inflammatory cytokines (IL-1β, IL-8, TNF-α and TGF-β) are suppressed or unchanged (GAPDH and γ-actin) (Lagger et al, EMBO J., 21: 2672-81, 2002; Richon et al, Clin. Cancer Res., 8: 662-667, 2002; Richon et al, Proc. Natl. Acad. Sci. USA., 97: 10014-9, 2000; Van Lint et al, Gene Expr., 5: 245-3, 1996; Huang et al, Cytokine, 9: 27-36, 1997; Mishra et al, Proc. Natl. Acad. Sci. USA., 98: 2628-33, 2001; Stockhammer et al, J. Neurosurg., 83: 672-81, 1995; Segain et al, Gut, 47: 397-403, 2000; Leoni et al, Proc. Natl. Acad. Sci. USA, 99: 2995-3000, 2002). In addition to inducing histone hyperacetylation, HDAC inhibitors also cause hyperacetylation of non-histone proteins such as ribosomal S3, p53, or the Rel-A subunit of NF-κB, and protein kinase C (PKC) activity , Inhibit protein isoprenylation, reduce DNA methylation and bind to nuclear receptors (Webb et al, J. Biol. Chem., 274: 14280-7, 1999; Chen et al, Science , 293: 1653-7, 2001). A number of different mechanisms have also been shown to inhibit NF-κB transcriptional activity following HDAC inhibitor treatment. HDAC inhibitors exhibit properties that induce cell cycle arrest, cell differentiation, and apoptotic cell death in tumor cells and reduce inflammatory responses in inflammatory diseases (Warrell et al, J. Natl. Cancer Inst., 90: 1621-5, 1998; Vigushin et al, Clin. Cancer Res., 7: 971-6, 2001; Saunders et al, Cancer Res., 59: 399-404, 1999; Gottlicher et al, EMBO J., 20: 6969-78, 2001; Rombouts et al, Acta Gastroenterol. Belg., 64: 239-46, 2001). The ability to modulate chromatin structure and NF-κB activity suggests that HDAC inhibitors can be therapeutic candidates not only for cancer but also for inflammatory diseases.

  Thus, based on the action of HDAC inhibitors, by using HDAC inhibitors, it suppresses major pro-inflammatory cytokines (TNF-α and IL-6) production, NF-κB activity, and inflammatory cell infiltration, Anti-inflammatory effects are expected in joint diseases. Drugs such as NSAIDs, steroids, DMARDs, and TNF-α antagonists aimed at anti-inflammatory or immunosuppression have not so far shown any effect to prevent joint damage, but surprisingly, in the present invention, HDAC inhibitors In addition to suppressing inflammation, it has been found that use can effectively prevent joint damage by inhibiting the degradation and resorption of bone and cartilage of the joint.

  The active compounds used to practice the invention are generally histone hyperacetylating agents such as HDAC inhibitors. Many such compounds are known. See, for example, P. Dulski, Histone Deacetylase as Target for Antiprotozoal Agents, PCT Application International Publication No. 97/11366 (March 27, 1997). Examples of such compounds include, but are not limited to:

A. Trichostatin A and its analogs, eg: Trichostatin A (TSA); and Trichostatin C (Koghe et al. 1998. Biochem. Pharmacol. 56: 1359-1364) (Trichostatin B has not been isolated Is not shown to be an HDAC inhibitor).

B. Peptides such as: oxamflatin [(2E) -5- [3-[(phenylsulfonyl) aminophenyl] -pent-2-en-4-inohydroxamic acid (Kim et al. Oncogene, 18 : 2461-2470 (1999)); Trapoxin A (TPX) -cyclic tetrapeptide (cyclo- (L-phenylalanyl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8-oxo) -9,10-epoxy-decanoyl)) (Kijima et al., J. Biol. Chem. 268, 22429-22435 (1993)); FR901228, depsipeptide (Nakajima et al., Ex. Cell Res. 241, 126- 133 (1998)); FR225497, cyclic tetrapeptide (H. Mori et al., PCT Application International Publication No. 00/08048 (February 17, 2000)); apicidin, cyclic tetrapeptide [cyclo ( NO-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)] (Darkin-Rattray et al., Proc. Natl. Acad. Sci. USA 93, 13143-13147 ( 1996)); Picidin 1a, Apicidin Ib, Apicidin Ic, Apicidin IIa, and Apicidin IIb (P. Dulski et al., PCT Application WO 97/11366); HC-Toxin, Cyclic tetrapeptide (Bosch et al., Plant Cell 7, 1941-1950 (1995)); WF27082, cyclic tetrapeptide (PCT application WO 98/48825); and chlamydocin (Bosch et al., supra).

C. Hydroxamic acid-based hybrid polar compounds (HPC), such as: salicylhydroxamic acid (SBHA) (Andrews et al., International J. Parasitology 30, 761-8 (2000)); suberoylanilide hydroxamic acid , SAHA) (Richon et al., Proc. Natl. Acad. Sci. USA 95, 3003-7 (1998)); azelaic bishydroxamic acid (ABHA) (Andrews et al., Supra); Azelaic-1-hydroxamate-9-anilide (AAHA) (Qiu et al., Mol. Biol Cell 11, 2069-83 (2000)); M-carboxycinnamic acid Bishydroxamide (CBHA) (Ricon et al., Supra); 6- (3-chlorophenylureido) carpoic hydroxamic acid, 3-Cl-UCHA (Richon et al MW2796 (Andrews et al., Supra); and MW2996 (Andrews et al., Supra). Note that the following analogs are not effective as HDAC inhibitors: hexamethylene bisacetamide (HBMA) (Richon et al. 1998, PNAS, 95: 3003-7); diethyl bix (pentamethylene-N, N-dimethyl) Carboxamide) malonate (EMBA) (Richon et al. 1998, PNAS, 95: 3003-7); pyroxamide, scriptaid, PXD-101, and LAQ-824.

D. Short chain fatty acid (SCFA) compounds such as: sodium butyrate (Cousens et al., J. Biol. Chem. 254, 1716-23 (1979)); isovalerate (McBain et al., Biochem. Pharm. 53: 1357 -68 (1997)); valproic acid; valerate (McBain et al., Supra); 4-phenylbutyric acid (4-PBA) (Lea and Tulsyan, Anticancer Research, 15, 879-3 (1995)); phenylbutyric acid ( PB) (Wang et al., Cancer Research, 59, 2766-99 (1999)); propionate (McBain et al., Supra); butyramide (Lea and Tulsyan, supra); isobutyramide (Lea and Tulsyan, supra); Phenylacetate (Lea and Tulsyan, supra); 3-bromopropionate (Lea and Tulsyan, supra); tributyrin (Guan et al., Cancer Research, 60, 749-55 (2000)); arginine butyrate Isobutyramide; and valproate.

E. benzamide derivatives such as: MS-27-275 [N- (2-aminophenyl) -4- [N- (pyridin-3-yl-methoxycarbonyl) aminomethyl] benzamide] (Saito et al., Proc. Natl. Acad. Sci. USA 96, 4592-7 (1999)); and 3'-amino derivatives of MS-27-275 (Saito et al., Supra); and CI-994.

F. Other inhibitors, such as: depudecin [analogs thereof (mono-MTM-depudecin and depudecin-bisether) do not inhibit HDAC] (Kwon et al. 1998. PNAS 95: 3356-61); and Scriptaide (Su et al. 2000 Cancer Research, 60: 3137-42).

  As used herein, the term histone deacetylase (HDAC) is an enzyme that catalyzes the removal of an acetyl group from a lysine residue in the amino tail of a nucleosomal core histone. Thus, HDAC regulates histone acetylation status with histone acetyltransferase (HAT). Histone acetylation affects gene expression, and inhibitors of HDACs such as the hydroxamic acid-based hybrid polar compound suberoylanilide hydroxamic acid (SAHA) may cause growth arrest, differentiation, and / or apoptosis of transformed cells in vitro And inhibit tumor growth in vivo. HDACs can be divided into three classes based on structural homology. Class I HDACs (HDACs 1, 2, 3, and 8) are similar to the yeast RPD3 protein, are located in the nucleus and are found in complexes associated with transcriptional corepressors. Class II HDACs (HDACs 4, 5, 6, 7, and 9) are similar to the yeast HDA1 protein and are localized both in the nucleus and in the cytoplasm in cells. Hydroxamic acid-based HDAC inhibitors such as SAHA inhibit both class I and II HDACs. Class III HDACs are nicotinamide (NAD) -dependent enzymes related to the yeast SIR2 protein, forming a structurally separated class that is not inhibited by hydroxamic acid-based HDAC inhibitors.

  As used herein, the term HDAC inhibitor is a compound capable of inhibiting histone deacetylation in vivo, in vitro, or both. Thus, the HDAC inhibitor inhibits the activity of at least one histone deacetylase. Inhibition of deacetylation of at least one histone results in an increase in acetylated histone and accumulation of acetylated histone is a suitable biological marker for assessing the activity of HDAC inhibitors . Thus, the HDAC inhibitory activity of the compound of interest can be measured using a technique that can assay the accumulation of acetylated histones. It is understood that compounds that can inhibit histone deacetylase activity can also bind to other substrates and inhibit other biologically active molecules such as enzymes or non-histone proteins.

  The HDAC inhibitor can also be in the form of a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts can be used as long as they do not adversely affect the desired pharmacological effect of the compound. Selection and manufacture can be made by those skilled in the art. Examples of pharmaceutically acceptable salts include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts with organic bases such as ammonium salts, or triethylamine salts or Examples thereof include salts having an organic base such as ethanolamine salt.

  The HDAC inhibitor of the present invention can be administered orally or parenterally. In the case of oral administration, it can be administered in the form of soft and hard capsules, tablets, granules, powders, solutions, suspensions, mouth washes and the like. For parenteral administration, it is administered in the form of cream, ointment, gel, lotion, patch, suppository, liposome preparation, injection solution, infusion preparation, enema, etc., solid, viscous solution, bioadhesive substance, or suspension In this form, continuous membrane absorption can be maintained. A method for preparing these preparations and a vehicle or carrier, disintegrant, or suspending agent can be easily selected by those skilled in the art. The bisphosphonates and HDAC inhibitors of the present invention can comprise additional compositions or other agents and a pharmaceutically acceptable carrier or pharmaceutically acceptable salt thereof.

  In another aspect of the invention, an HDAC inhibitor is combined with an organic bisphosphonate to treat, prevent, or reduce the risk of joint damage. Bisphosphonates are potent bone resorption inhibitors used for the treatment and prevention of osteoporosis. Overall, bisphosphonates have in common a P—C—P structure similar to that of natural pyrophosphate. Bisphosphonates differ from each other only by two “R” groups. Examples of such compounds include alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, orpane Listed include olpandronate, risedronate, piridronate, pamidronate, and zolendronate (Rodan, GA., Et al., J. Clin. Nvest. 97: 2692, 1996) However, it is not limited to them. Bisphosphonates inhibit osteoclastic bone resorption through a different mechanism than that of other resorption inhibitors such as estrogens. Bisphosphonates adhere to body surfaces, particularly those that are actively absorbed. When osteoclasts begin to resorb bone filled with bisphosphonates, the bisphosphonates released during resorption make the boundaries jagged, adhere to the bone surface, and generate the protons necessary for continued bone resorption. Reduce cell capacity (Colucci, S., et al., Calcif. Tissue Int. 63: 230, 1998). In addition to releasing bisphosphonates from bone surfaces via resorption, bisphosphonate mechanisms that reduce osteoclast activation include inhibition of IL-6 production, promotion of osteoblast precursor formation, osteoclast precursors Inhibition of osteoclast cholesterol synthesis through inhibition of somatic proliferation, induction of apoptosis in osteoclasts, and inhibition of the enzyme farnesyl diphosphate synthase (Reszka, AA., Et al., J. Biol. Chem. 274: 34967 1999; Tokuda, H., et al., J. Cell Biochem. 69: 252, 1998). Thus, the combined use of HDAC inhibitors and bisphosphonates relates to other aspects of the invention for preventing joint damage in more destructive diseases such as rheumatoid arthritis, degeneration, trauma, and cancer.

  As will be appreciated by those skilled in the art, effective doses are determined by the route of administration, the use of excipients, and other treatments such as second HDAC inhibitors, organic bisphosphonates, chemotherapeutic agents, radiopharmaceuticals, TNF- alpha antagonist, non-steroidal anti-inflammatory drug, steroid, antioxidant, angiogenesis inhibitor, matrix metalloproteinase inhibitor, vitamin, selective estrogen receptor modulator (SERM), estrogen-progestin, androgen, calcitonin, antibiotics, Cathepsin K inhibitor, inhibitor of osteoclast proton ATPase, inhibitor of HMG-CoA reductase, statin, integrin receptor antagonist, osteoblast anabolic agent, or selective serotonin reuptake inhibitor, or pharmaceutically thereof It depends on the possibility of combined use, such as the use of acceptable salts or mixtures. Effective amounts and treatment regimens for any particular subject (eg, human, dog, or cat) will also depend on the activity, age, weight, overall health, sex, diet, time of administration, excretion of the particular compound used. Depending on the rate, severity and course of the disease, and various other factors including the patient's predisposition to the disease, it is usually 0.001% to 100% of the weight of the composition, regardless of the mode of administration. The active compounds of the present invention optionally treat, prevent, or prevent joint damage in subjects suffering from joint or musculoskeletal diseases such as spondyloarthritis, rheumatoid arthritis, and other destructive joint diseases resulting from trauma, degeneration, or cancer It may be administered with other compounds useful in reducing that risk. These other compounds may optionally be administered simultaneously or sequentially. As used herein, the term “simultaneously” means sufficiently close in time to produce a combined effect (ie, simultaneous may be simultaneous or each is in a short period of time. It may be two or more events that occur before and after). As used herein, “simultaneous” or “combination” administration of two or more compounds is sufficiently close in time that the presence of one changes the biological effect of the other. Means to be administered. The two or more compounds may be administered simultaneously or sequentially. Co-administration may be accomplished by mixing the compounds prior to administration, or by administering the compounds at the same time at different anatomical locations or using different routes of administration.

  In order that the invention described herein may be more readily understood, the following examples are set forth. It should be understood that the examples are for illustrative purposes only and should not be construed as limiting the invention in any way. All documents cited herein are expressly incorporated by reference in their entirety.

Example
Example 1: Prevention of joint damage Animal models of destructive joint disease have been created and well characterized (Winter CA, et al., Arthritis Rheum. 9: 394-404, 1966). Long Evans rats weighing 150 ± 20 g and ICR-derived male mice weighing 22 ± 2 g were used. Space allocation was 45 x 23 x 15 cm for 5 mice. Animals are housed in APEC® (Allentown Gaging, Allentown, NJ, USA) cages, hygienic with controlled temperature (22-24 ° C) and humidity (60-80%), 12 hour light / dark cycle Maintained for at least one week in a dynamic environment. Micropowder suspension of dead M. tuberculosis (DIFCO, USA; 0.3 mg, in 0.1 ml light mineral oil; complete Freund's adjuvant (CFA) on the first day (first day) of HDAC inhibitor Immediately after administration, it was administered into the plantar region of the right hind limb.A topical formulation containing an HDAC inhibitor was previously made by the inventors (Chung, YL., Et al., Mol. Cancer Ther. 3 : 317-325, 2004) 1% sodium phenylbutyrate cream (HDAC inhibitor) at a dose of 200 mg / limb, or 0.1% trichostatin A (HDAC inhibitor) ointment at a dose of 10 mg / limb, right hind limb surface The whole body was applied topically twice a day for 18 consecutive days.The volume of the hind limbs was measured by Plethsmometer (Cat. No. 7150, UGO BASILE, Italy) and Water cell (diameter 25 mm, Cat. No. 7157, UGO BASILE , Italy), measured on day 0 (before CFA treatment), right limb after CFA (with CFA) on days 1, 5, 10, and 15. On day 18, the right hind limb was blanked and Removed from the vehicle control group as well as the treatment group, each group had 6 animals, a portion of the freshly removed tissue was subjected to Northern blot analysis for TNF-α expression levels in the joints, and the tissue was 10% phosphorous. Fixed in acid buffered formalin (pH 7.4), decalcified with 10% EDTA, embedded in paraffin, sections (thickness 3 μm) stained with hematoxylin and eosin (H & E) and immunostained with p16INK4 antibody Then, the joint structure was examined.

The results were as follows:
a. HDAC inhibitors suppress joint swelling.
As shown in FIGS. 1A and 1B, the HDAC inhibitor more significantly suppresses ankle swelling compared to the control group, suggesting an anti-inflammatory effect.

b. HDAC inhibitors down regulate the expression of the proinflammatory cytokine TNF-α in the joint.
As shown in FIG. 2, Northern blots show that HDAC inhibitors down-regulate TNF-α expression at the transcriptional level in joint tissues, which correlates with anti-inflammatory effects.

c. HDAC inhibitors up-regulate cell cycle inhibitors in cells lining the joint capsule.
A representative example of an immunohistochemical analysis of the cell cycle inhibitor p16INK4 shown in Figure 3B shows that HDAC inhibitors selectively upregulate p16INK4 expression in the synovium lining the joint capsule. This suggests that it has the effect of inhibiting synovial proliferation and invasion. FIG. 3A is an H & E staining of the joint space.

d. HDAC inhibitors prevent joint damage by reducing cartilage and bone degradation and resorption.
As shown in FIG. 4B, gross sections show that the entire right hind limb joint is well preserved in the HDAC inhibitor treated group compared to the blank control shown in FIG. 4A. Furthermore, from the pathological findings in FIGS. 5B and 6B, compared to the blank controls shown in FIGS. 5A and 6A, respectively, HDAC inhibitors showed joint damage from inflammatory cell infiltration, synovial invasion, cartilage degradation, and bone resorption. Is confirmed to prevent.

Example 2: Prevention of cartilage resorption
It has been shown that the combination of IL-1α and oncostatin M (OSM, IL-6 type cytokine) promotes cartilage damage (Cawston TE., Et al., Arthritis Rheum. 41: 1760-1771, 1998 ). To demonstrate the ability of HDAC inhibitors to reduce cartilage resorption induced by IL-1α and OSM, a bovine nasal cartilage explant assay was performed. Cartilage explants were cultured with IL-1α (5 ng / ml) and OSM (10 ng / ml) and treated with sodium phenylbutyrate (0-8 mM) or trichostatin A (0-400 ng / ml) for 12 hours. The rate of collagen release from the cartilage explant to the conditioned medium indicates the extent of cartilage resorption. As shown in FIG. 7, the HDAC inhibitors sodium phenylbutyrate and trichostatin A suppress collagen loss from cartilage. This result indicates that HDAC inhibitors can prevent irreversible resorption of cartilage.

Other Embodiments From the above, those skilled in the art can readily ascertain the essential characteristics of the present invention and various modifications of the present invention to adapt to various uses and conditions without departing from the spirit and scope thereof. Changes and modifications can be made. For example, compounds that are structurally and functionally similar to the HDAC inhibitors described above can also be used to practice the present invention. Thus, other embodiments are also within the claims.

  While the invention has been described in terms of preferred embodiments by way of example, it is to be understood that the invention is not limited thereto.

1A and 1B show the effect of HDAC inhibitors in suppressing joint swelling in an animal model of destructive joint disease. FIG. 1A shows the net swelling of limb volume for blank controls, cream vehicle, and phenylbutyric acid cream treatment on various days, and FIG. 1B is for ointment control and trichostatin A ointment treatment on various days Indicates. FIG. 5 is a Northern blot result showing that the expression of the major pro-inflammatory cytokine TNF-α is greatly suppressed at the transcriptional level in joints treated with HDAC inhibitors. FIGS. 3A and 3B are histological staining results showing that HDAC inhibitors up-regulate cell cycle inhibitors in cells lining the joint capsule. FIG. 3A shows H & E staining, and FIG. 3B shows the results of p16 ^INK4 immunohistochemical analysis. 3A and 3B are 200 × fields. 4A and 4B are macroscopic sections of limb joints showing that HDAC inhibitors preserve joint structure. FIG. 4A is a control group, and FIG. 4B is an HDAC inhibitor treatment group. The black arrow indicates a damaged ankle joint in the control group. FIGS. 5A and 5B are histological staining results showing that HDAC inhibitors prevent joint damage. FIG. 5A is the control group, and FIG. 5B is the HDAC inhibitor treatment group. Black arrows indicate degradation and resorption in joint cartilage and bone due to proliferative synovial invasion in the control group. 5A and 5B are 40 × fields. 6A and 6B are histological staining results showing that the joint capsule is well protected by HDAC inhibitors. FIG. 6A is a control group, and FIG. 6B is an HDAC inhibitor treatment group. Black arrows indicate the location of inflammatory cell infiltration and bone degradation within the damaged joint in the control group. 6A and 6B are 100 × fields. HDAC inhibitors sodium phenylbutyrate and trichostatin A reduce IL-α and oncostatin M (OSM, IL-6 type cytokine) -induced collagen release in bovine nasal cartilage explant cultures, and HDAC inhibitors It is a figure which shows that possibility of preventing cartilage resorption was suggested.

Claims (29)

  Joint or musculoskeletal in a subject in need of inhibiting the degradation and resorption of joint cartilage and bone, comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier A pharmaceutical composition for preventing joint damage of a disease.   2. The pharmaceutical composition according to claim 1, wherein the HDAC inhibitor is a hydroxamic acid derivative, a short chain fatty acid (SCFA), a cyclic tetrapeptide, a benzamide derivative, or an electrophilic ketone derivative.   Hydroxamic acid derivatives include suberoylanilide hydroxamic acid (SAHA), pyroxamide, M-carboxycinnamic acid bishydroxamide (CBHA), trichostatin A (TSA), trichostatin C, salicylhydroxamic acid (SBHA), azela Icbishydroxamic acid (ABHA), azelic 1-hydroxamate-9-anilide (AAHA), 6- (3-chlorophenylureido) carpoic hydroxamic acid (3Cl-UCHA), oxamflatin, A-161906, scriptaid, The pharmaceutical composition according to claim 2, selected from the group consisting of PXD-101, LAQ-824, cyclic hydroxamic acid-containing peptide (CHAP), MW2796, and MW2996.   The pharmaceutical composition according to claim 2, wherein the cyclic tetrapeptide is selected from the group consisting of trapoxin A, FR901228 (FK 228 or depsipeptide), FR225497, apicidin, CHAP, HC-toxin, WF27082, and clamidosine.   Short chain fatty acids (SCFA) are sodium butyrate, isovalerate, valerate, 4-phenylbutyric acid (4-PBA), sodium 4-phenylbutyrate (PBS), arginine butyrate, propionate, butyramide, isobutyramide, phenylacetate, 3- The pharmaceutical composition according to claim 2, selected from the group consisting of bromopropionate, tributyrin, valproic acid, and valproate.   The pharmaceutical composition according to claim 2, wherein the benzamide derivative is selected from the group consisting of CI-994, MS-27-275 (MS-275), and 3'-amino derivative of MS-27-275.   3. The pharmaceutical composition according to claim 2, wherein the electrophilic ketone derivative is trifluoromethyl ketone or alpha-ketoamide.   2. The pharmaceutical composition according to claim 1, wherein the HDAC inhibitor is depudecin.   2. The pharmaceutical composition according to claim 1, wherein the joint disease is spondyloarthropathy.   Spondyloarthropathies from undifferentiated spondyloarthropathy, ankylosing spondylitis, juvenile ankylosing spondylitis, reactive arthritis, Reiter syndrome, psoriatic arthropathy, and spondyloarthropathy associated with Crohn's disease and ulcerative colitis 10. The pharmaceutical composition according to claim 9, which is selected from the group consisting of:   2. The pharmaceutical composition according to claim 1, wherein the joint disease is peripheral oligoarthritis, tendinitis, HLA-B27-related reactive arthritis, synovitis, or extrasynovitis.   2. The pharmaceutical composition according to claim 1, wherein the joint disease is rheumatoid arthritis.   Joint disease is bone loss, fracture, osteonecrosis, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, Paget's disease, Gossy disease, sickle cell anemia, osteomyelitis, abnormally increased bone turnover, osteoclastic surgery 2. The pharmaceutical composition of claim 1, selected from the group consisting of: periodontal disease, osteolysis around a prosthetic device, degenerative joint disease, osteoarthritis, gouty arthritis, septic arthritis, and osteogenesis imperfecta.   Osteoporosis or osteopenia is immobilization, bone dysplasia, cachexia, anorexia nervosa, exercise-induced amenorrhea, chemotherapy or radiation therapy-induced amenorrhea, androgen deprivation therapy, Turner syndrome, cyst For fibrosis, diabetes, hyperthyroidism, hyperparathyroidism, Cushing syndrome, glucocorticoid excess, acute lymphoblastic leukemia, Klinefelter and Kalman syndrome, alcohol abuse, smoking, connective tissue disease, or osteoarthritis 14. A pharmaceutical composition according to claim 13, which subsequently occurs secondarily.   The joint disease is a joint injury caused by bone cancer, multiple myeloma, malignant hypercalcemia, metastatic bone disease, paraneoplastic syndrome, trauma, surgery, chemotherapy, or radiation therapy. A pharmaceutical composition as described.   Second HDAC inhibitors, organic bisphosphonates, chemotherapeutic agents, radiopharmaceuticals, TNF-α antagonists, non-steroidal anti-inflammatory drugs, steroids, antioxidants, angiogenesis inhibitors, matrix metalloproteinase inhibitors, vitamins, selective estrogens Receptor modulator (SERM), estrogen-progestin, androgen, calcitonin, antibiotics, cathepsin K inhibitor, osteoclast proton ATPase inhibitor, HMG-CoA reductase inhibitor, statin, integrin receptor antagonist, bone The pharmaceutical composition of claim 1, further comprising an agent selected from the group consisting of a blast anabolic agent, or a selective serotonin reuptake inhibitor, and a pharmaceutically acceptable salt or mixture thereof.   17. The pharmaceutical composition of claim 16, wherein the vitamin is selected from the group consisting of nicotinamide, vitamin B complex, vitamin C, vitamin D, and vitamin E.   17. The pharmaceutical composition of claim 16, wherein the agent is provided prior to the HDAC inhibitor.   17. The pharmaceutical composition of claim 16, wherein the agent is provided after the HDAC inhibitor.   17. The pharmaceutical composition according to claim 16, wherein the agent is supplied simultaneously with the HDAC inhibitor.   The drug is administered orally, intra-articularly, intraperitoneally, intrathecally, intraarterial, intranasal, intraparenchymal, subcutaneous, intramuscular, intravenous, intradermal, rectal, or topically. Item 16. A pharmaceutical composition according to Item 16.   A histone deacetylase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are cream, gel, ointment, paste, mouthwash, powder, tablet, pill, granule, capsule, lotion 17. The pharmaceutical composition of claim 16, formulated as a suspension, liposome formulation, nanoparticle, patch, suppository, enema, infusion, or injection.   17. The pharmaceutical composition of claim 16, wherein the agent is provided by a different route than the HDAC inhibitor.   Treatment, prevention, or risk of joint damage in joint or musculoskeletal diseases comprising a histone deacetylase (HDAC) inhibitor, an organic bisphosphonate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier A pharmaceutical composition for reducing blood pressure.   The bisphosphonate is selected from the group consisting of alendronate, simadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, pyridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts or mixtures thereof 25. A pharmaceutical composition according to claim 24.   Joint disease, spondyloarthritis, rheumatoid arthritis, bone loss, fracture, osteonecrosis, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, Paget's disease, Goshe's disease, sickle cell anemia, osteomyelitis, abnormally increased Bone turnover, osteoclastic, periodontal disease, osteolysis around prosthesis, degenerative joint disease, osteoarthritis, gouty arthritis, septic arthritis, osteogenesis imperfecta, bone cancer, multiple myeloma, malignant high 25. The pharmaceutical composition of claim 24, wherein the composition is calcemia, metastatic bone disease, or paraneoplastic syndrome.   Osteoporosis or osteopenia is immobilization, bone dysplasia, cachexia, anorexia nervosa, exercise-induced amenorrhea, chemotherapy or radiation therapy-induced amenorrhea, androgen deprivation therapy, Turner syndrome, cystic fibrosis , Diabetes, hyperthyroidism, hyperparathyroidism, Cushing syndrome, glucocorticoid excess, acute lymphoblastic leukemia, Klinefelter and Kalman syndrome, alcohol abuse, smoking, connective tissue disease, or osteoarthritis 27. The pharmaceutical composition of claim 26, which occurs next.   25. The pharmaceutical composition of claim 24, wherein the joint disease is a joint injury caused by trauma, surgery, chemotherapy, or radiation therapy.   Second HDAC inhibitor, second bisphosphonate, chemotherapeutic agent, radiopharmaceutical, TNF-α antagonist, nonsteroidal anti-inflammatory drug, steroid, antioxidant, angiogenesis inhibitor, matrix metalloproteinase inhibitor, vitamin, selection Estrogen receptor modulator (SERM), estrogen-progestin, androgen, calcitonin, antibiotics, cathepsin K inhibitor, osteoclast proton ATPase inhibitor, HMG-CoA reductase inhibitor, statin, integrin receptor antagonist 25. The pharmaceutical composition of claim 24, further comprising an agent selected from the group consisting of: an osteoblast anabolic agent, or a selective serotonin reuptake inhibitor, and a pharmaceutically acceptable salt or mixture thereof.

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