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WO2016040650A1 - Effets d'inhibition de la guanylyl cyclase soluble sur le système vasculaire lymphatique - Google Patents

Effets d'inhibition de la guanylyl cyclase soluble sur le système vasculaire lymphatique Download PDF

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WO2016040650A1
WO2016040650A1 PCT/US2015/049450 US2015049450W WO2016040650A1 WO 2016040650 A1 WO2016040650 A1 WO 2016040650A1 US 2015049450 W US2015049450 W US 2015049450W WO 2016040650 A1 WO2016040650 A1 WO 2016040650A1
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bis
oxadiazolo
amino
lymphatic
azanediyl
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Edward M. Schwarz
Christopher T. Ritchlin
Homaira RAHIMI
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University of Rochester
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University of Rochester
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • sGC soluble guanylyl cyclase
  • Juvenile idiopathic arthritis is the most common rheumatic condition in childhood, with a prevalence of 16 to 150 per 100,000 in developed countries (Ravelli et al., "Juvenile Idiopathic Arthritis," Lancet. 369(9563): 767-78 (2007)).
  • JIA Juvenile idiopathic arthritis
  • a 2007 CDC study estimated a staggering one hundred thousand children seen for inflammatory polyarthropathies and synovitis (Sacks et al., "Prevalence of and Annual Ambulatory Health Care Visits for Pediatric Arthritis and Other Rheumatologic Conditions in the United States in 2001-2004," Arthritis Rheum.
  • a first aspect of the disclosure relates to a method of treating an inflammatory joint flare in a subject that includes: selecting a subject having an inflammatory joint flare and administering to said subject a soluble guanylyl cyclase ("sGC”) inhibitor in an amount effective to treat the inflammatory joint flare.
  • sGC soluble guanylyl cyclase
  • a second aspect of the disclosure relates to a method of treating a condition associated with a decreased lymphatic pulse that includes: selecting a subject having a decreased lymphatic pulse and administering to said subject an sGC inhibitor in an amount effective to increase the lymphatic pulse thereby treating said condition.
  • a third aspect of the disclosure relates to a method of treating an inflammatory joint condition that includes: selecting a subject having an inflammatory joint condition and administering to the subject an effective amount of an sGC inhibitor.
  • a fourth aspect of the disclosure relates to a pharmaceutical composition that includes a pharmaceutically acceptable carrier, an sGC inhibitor, and one or more additional therapeutic agents suitable for treatment of inflammatory joint flare, decreased lymphatic pulse, or an inflammatory joint condition.
  • a fifth aspect of the disclosure relates to a therapeutic system that includes a first pharmaceutical composition comprising a pharmaceutically acceptable carrier and an sGC inhibitor; and a second pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more additional therapeutic agents suitable for treatment of inflammatory joint flare, decreased lymphatic pulse, or an inflammatory joint condition.
  • lymphatics are a biomarker of arthritic flare, and provide evidence demonstrating that the nitric oxide/sGC receptor signaling pathway may be a key regulator of lymphatic function.
  • sGC inhibitors is shown to be successful in promoting lymphatic function (e.g., restoration of lymphatic pulse), which alone or in combination with other therapies should substantially improve the efficacy of arthritis treatments and treatments of other inflammatory conditions.
  • Figures 1A-1D show representative MRI and corresponding 3D volume renderings of the knee.
  • Figure 1 A is a T2 fat-suppressed MRI image of an early rheumatoid arthritis ("RA") patient with asymmetric arthritic knee flare and increased lymphatic flow.
  • Figure IB shows the 3D volume rendering of the inflammatory tissue (red; arrowhead) and large popliteal lymph node (“PLN”) (blue, green, and yellow; arrows) corresponding to the 3D image of the early RA patient.
  • Figure 1 C is a proton density weighted MRI image of a late RA patient with asymmetric knee flare and decreased lymphatic flow.
  • Figure ID shows the 3D volume rendering of the inflammatory tissue (red; arrowhead) and collapsed PLN (blue, yellow; arrows) corresponding to the 3D image of the late RA patient.
  • Figures 2A-2J show representative histology and immunohistochemistry staining of the medial cross-section of the PLN.
  • PLN tissue was harvested from either RA patients during total knee replacement surgery ( Figures 2A-2E) or from human amputated legs that had evidence of knee osteoarthritis ( Figures 2F-2J).
  • H&E stained histology of the medial cross section of the PLN was photographed at 1.25X magnification ( Figures 2A and 2F).
  • Figures 2B and 2G show the evaluation of knee synovial volume and lymphatic pulse following B-cell depletion. Lymphatic drainage was evaluated in tumor necrosis factor- transgenic ("TNF-Tg") mice prior to ( Figures 3A-3B) and following ( Figures 3C-3D) treatment with anti-CD20.
  • Figure 3E shows knee synovial volume measured in mice treated with placebo or a-CD20.
  • Figure 3F shows the lymphatic pulse of mice treated with anti-CD20.
  • Figures 4A-4C show the co-localization of soluble guanylyl cyclase and alpha- smooth actin ("SMA") in PLN. Immunofluorescent microscopy was performed on fresh frozen histology sections of the PLN from TNF-Tg mice. Histology sections were stained for GCal ( Figure 4A, red), a2 ( Figure 4B, red), GC i ( Figure 4C, red), and SMA ( Figures 4A-4C, green). Co-localization is shown in Figures 4A-4C.
  • SMA alpha- smooth actin
  • FIGs 5A-5D illustrate the increase in Indocyanine Green (“ICG”) uptake by lymphatic vessels with sGC inhibitor treatment.
  • Figures 6A-B show the altered lymphatic rhythm and increased lymphatic pulse in mice treated with sGC inhibitor compared to control.
  • Figure 6A is a representative graph of lymphatic pulse with control versus sGC inhibitor.
  • Figure 6B shows the measured lymphatic pulse in control and sGC inhibitor treated mice.
  • FIGS 7A-7F show that Gr-1+ cells are present in afferent lymphatic vessel to collapsed PLN and highly express iNOS.
  • FITC fluorescein isothiocyanate
  • FIGS. 7A- 7B show immunofluorescence microscopic images of a representative lymphatic vessel afferent to the collapsed PLN, showing CD1 lb + cells ( Figure 7A) and Gr-1 + cells ( Figure 7B).
  • Figures 8A-8B are schematics of NO/sGC signaling in lymphatics during normal and inflamed conditions, as evidenced by the preceding results.
  • NO produced by eNOS in lymphatic endothelial cells (“LECs”) in response to increased shear stress diffuses to the SMC layer of lymphatic collecting vessels and binds to sGC receptor, leading to dilation of the vessel. Dilation results in decreased shear stress turning off the eNOS signal to produce NO. Remaining NO diffuses away and the vessel contracts.
  • iNOS + cells produce overwhelming amounts of NO, over-riding the normal process so that NO is continuously present, resulting in persistently dilated vessels that are unable to pulse. sGC inhibition prevents NO binding to its receptor and results in restoration of the pulse.
  • Figures 9A-9C show the contractility in lymphatics of TNF-Tg mice. Lymphatic collecting vessels were isolated and cannulated from TNF-Tg mice for ex vivo analysis in the absence (Figure 9B) and presence (Figure 9C) of Ca + channel blocker BayK8644.
  • Figure 9A shows TNF-Tg popliteal collecting lymphatic vessels tied to two glass pipettes for pressure control.
  • Figures 9B-C show the raw tracing of TNF-Tg lymphatic contractions during a pressure step protocol. Input and output pressures (cmFtO, blue and red, respectively) are displayed on the top trace and are overlaid because they were changed simultaneously from 0.5 to 1, 2, 3, 5, 7, and 10 cmF ⁇ O. The bottom traces plot the inner diameter ( ⁇ ) measured continuously over time.
  • patient and “subject” are used synonymously, and are intended to refer to any animal that exhibits an inflammatory condition that is amenable to treatment in accordance with the methods disclosed herein.
  • the patient is a mammal.
  • exemplary mammalian patients include, without limitation, humans, non-human primates, dogs, cats, rodents (e.g., mouse, rat, guinea pig), horses, cattle and cows, sheep, and pigs.
  • the inflammatory condition to be treated using the methods disclosed herein include, but are in no way limited to, rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, psoriasis, acute pancreatitis, allograph rejection, allergic inflammation, inflammatory bowel disease, septic shock, osteoporosis, and cognitive deficits induced by neuronal inflammation.
  • RA rheumatoid arthritis
  • juvenile idiopathic arthritis juvenile idiopathic arthritis
  • psoriatic arthritis ankylosing spondylitis
  • insulin-dependent diabetes mellitus multiple sclerosis
  • myasthenia gravis Crohn's disease
  • autoimmune nephritis primary biliary cirrhos
  • the inflammatory condition is one that affects the joint, i.e., involves inflammation in or around the joint.
  • Inflammatory conditions of the joint include rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, gout, psoriatic arthritis, ankylosing spondylitis, Reiter's syndrome, adult Still's disease, viral arthritis, bacterial arthritis, and tuberculous arthritis.
  • the treatment of an inflammatory joint condition includes (1) preventing the inflammatory joint condition, for example, preventing an inflammatory joint disease, condition or disorder in an individual that may be predisposed to the inflammatory joint disease, condition or disorder but does not yet experience or display the pathology or symptoms of such inflammatory joint disease, condition or disorder; (2) inhibiting the inflammatory joint condition, for example, inhibiting an inflammatory joint disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the inflammatory joint disease, condition or disorder (i.e., arresting further development of the pathology and/or symptoms or, alternatively, slowing progression of further development of the pathology or symptoms); and (3) ameliorating the inflammatory joint condition, for example, ameliorating an inflammatory joint disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of inflammatory joint disease, condition or disorder (i.e., reversing the pathology and/or symptoms).
  • the treatment of the inflammatory joint condition may include preventing, inhibiting, or ameliorating one or more symptoms of the inflammatory joint condition (e.g., joint flare) as well as promoting other functions such as lymphatic pulse.
  • Promoting lymphatic pulse connotes both reestablishment of lymphatic pulse in a region of the body where such pulse is/was lacking altogether, or enhancing the frequency of the lymphatic pulse in a region of the body where such pulse is/was diminished (i.e., relative to what would be considered normal across all individuals or normal for an individual patient prior to onset of the symptoms).
  • the therapeutic agents include an inhibitor or antagonist of soluble guanylyl cyclase ("sGC").
  • sGC is a heme-containing enzyme that regulates cardiovascular homeostasis and multiple mechanisms in the central and peripheral nervous system.
  • sGC heterodimer is composed of an a-subunit and a shorter ⁇ -subunit which presents in the N-terminal the prosthetic heme group bound to histidine-105.
  • Each subunit is composed of a heme -nitric oxide binding domain, a PAS-like domain, a coiled-coil bundle, and the C-terminal catalytic domain where turnover of GTP into cGMP occurs (Cary et al., Trends Biochem.
  • the catalytic domain of sGC shows two sites at the interface of the a- and ⁇ -subunits that can accommodate small molecules: the GTP binding site, and an allosteric regulatory binding site (Allerston et al., PloS One 8:e57644 (2013); Zhang et al., Protein Sci. 6:903 (1997); Stasch et al., Nature 410:212 (2001), each of which is hereby incorporated by reference in its entirety).
  • the two sites are different, and small molecules can bind to one or to both sites, thus showing a 1 : 1 or 1 :2 binding ratio.
  • sGC inhibitors include those that inhibit sGC activity act through oxidation of the heme moiety and those that bind directly to the catalytic domain of the enzyme.
  • Exemplary sGC inhibitors or antagonists that act via oxidation of the heme moiety include, without limitation, 3,7-bis(Dimethylamino)phenothiazin-5-ium (methylene blue); 6- anilino-5,8-quinolinedione (or LY-83583); [lH-l,2,4]oxadiazolo[4,3-a]quinoxalin-l-one (or ODQ) (Moro et al., Proc. Natl. Acad. Sci.
  • Exemplary sGC inhibitors or antagonists that bind directly to the catalytic domain of the enzyme include, without limitation, oxadiazolo[3,4-£]pyrazines and N2,N3- diphenylquinoxaline-2,3 -diamines as well as other compounds of the type described in Mota et al., Bioorg. Med. Chem. 23(17):5303-5310 (2015), which is hereby incorporated by reference in its entirety.
  • Exemplary sGC inhibitors identified by Mota et al. include the following:
  • sGC inhibitors that bind directly to the enzyme can be identified using, e.g., a surface plasmon resonance-based assay with either full-length sGC or a smaller construct of the catalytic domain (sGCcat), as described in Mota et al., Bioorg. Med. Chem. Lett. 24: 1075 (2014), which is hereby incorporated by reference in its entirety. Screening of such agents that bind the catalytic domain for inhibition of sGC can then be carried out using the soluble guanylate cyclase assay to assess cGMP production, as described by Mota et al. ⁇ Bioorg. Med. Chem. Lett. 24:1075 (2014)) or Olesen et al. (Br. J. Pharmacol. 123:299 (1998)), each of which is hereby incorporated by reference in its entirety.
  • additional agents in combination with sGC inhibitors or antagonists is also contemplated.
  • additional agents include, without limitation, VEGFR-3 agonists or gene therapy agents as described U.S. Patent No. 8,580,755 to Xing et al., which is hereby incorporated by reference in its entirety; VEGF inhibitors that inhibit VEGF directly or interfere with its signaling through VEGFR 1 or R2; traditional anti-inflammatory medication; steroid agents such as prednisone in various forms including orally or intra-articularly; an inhibitor of TNF-a; or a combination of any two or more thereof.
  • Exemplary VEGF inhibitors include, without limitation, antibodies directed to VEGF, VEGFR1 , VEGFR2, or the VEGF- VEGFR 1 or VEGF-VEGFR2 complex are described in U.S. Patent Publication No. 20020032313 to Ferrara et al., which is hereby incorporated by reference in its entirety; soluble VEGFR1 and R2 as set forth in U.S. Patent Publication No. 20030120038 to Kendall et al., which is hereby incorporated by reference in its entirety;
  • inhibitory VEGF variant proteins as described in U.S. Patent Publication Nos. 20060286636 to Shima et al. and 20050154187 to Shou et al., which are hereby incorporated by reference in their entirety; inhibitory fusion proteins directed to VEGF and VEGFR molecules as described in U.S. Patent Publication No.
  • VEGF Trap aptamers against VEGF (see Ng et al., "Pegaptanib, A Targeted Anti- VEGF Aptamer for Ocular Vascular Disease,” Nat Rev Drug Discovery 5(2): 123-32 (2006), which is hereby incorporated by reference in its entirety); and small molecule inhibitors of VEGF, VEGFR1, or VEGFR2 such as CP-547,632 (Pfizer Inc., NY, USA), AG13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788 (Novartis), AZD-2171), VEGF Trap
  • Vatalanib also known as PTK-787, ZK-222584: Novartis & Schering AG
  • IM862 Cytran Inc. of Kirkland, Wash., USA
  • angiozyme a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif); and the compounds disclosed in
  • Exemplary anti-inflammatory medications include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, glucocorticoids, disease modifying anti-rheumatic drugs, dihydrofolate reductase inhibitors (e.g., methotrexate), biologic response modifiers, and any combination thereof.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • analgesics e.g., glucocorticoids
  • glucocorticoids e.g., glucocorticoids
  • disease modifying anti-rheumatic drugs e.g., methotrexate
  • biologic response modifiers e.g., methotrexate
  • NSAIDs include cyclooxygenase-2 (COX-2) inhibitors, non-limiting examples of which include nimesulide, 4-hydroxynimesulide, flosulide, meloxicam, celecoxib, and Rofecoxib (Vioxx), as well as non-selective NSAIDS such as diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac and tolmetin.
  • COX-2 cyclooxygenase-2
  • Exemplary analgesics include, without limitation, acetaminophen, oxycodone, tramadol, and propoxyphene hydrochloride.
  • Exemplary glucocorticoids include, without limitation, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.
  • Exemplary biological response modifiers include B-cell inhibitors, such as rituximab, or T cell activation inhibitors such as leflunomide, etanercept (Enbrel), or infliximab (Remicade).
  • B-cell inhibitors such as rituximab
  • T cell activation inhibitors such as leflunomide, etanercept (Enbrel), or infliximab (Remicade).
  • Exemplary TNF-a inhibitors include anti-TNF-a antibody, a matrix
  • metalloproteinase inhibitor a corticosteroid, a tetracycline TNF-a antagonist, a fluoroquinolone TNF-a antagonist, and a quinolone TNF-a antagonist.
  • TNF-a antibodies include, without limitation, infliximab, etanercept,
  • CytoFAb, AGT-1, afelimomab, PassTNF, and CDP-870 are examples of CDP-870.
  • corticosteroids include, without limitation, mometasone, fluticasone, ciclesonide, budesonide, beclomethasone, beconase, flunisolide, deflazacort, betamethasone, methyl-prednisolone, dexamethasone, prednisolone, hydrocortisone, Cortisol, triamcinolone, cortisone, corticosterone, dihydroxycortisone, beclomethasone dipropionate, and prednisone.
  • Exemplary tetracycline TNF-a antagonists include, without limitation, doxycycline, minocycline, oxytetracycline, tetracycline, lymecycline, and 4-hydroxy-4- dimethylaminotetracycline .
  • Exemplary fluoroquinolone TNF-a antagonists include, without limitation, norfloxacin, ofloxacin, ciprofloxacin, lomefloxacin, gatifloxacin, perfloxacin, and temafloxacin.
  • Exemplary quinolone TNF-a antagonists include, without limitation, vesnarinone and amrinone.
  • TNF-a antagonists include, without limitation, thalidomide, Onercept,
  • Pegsunercept interferon-gamma, interleukin-1, pentoxyphylline, pimobeddan, lactoferrin, melatonin, nitrogen oxide, napthopyridine, a lazaroid, hydrazine sulfate, ketotifen, tenidap, a cyclosporin, peptide T, sulfasalazine, thorazine, glycyrrhizin, and L-carnitine.
  • the therapeutic agents described herein may be administered in any suitable manner or medically-accepted means for introducing a therapeutic directly or indirectly into a subject, including but not limited to orally, subcutaneously, intravenously, intramuscularly, parenterally, intrasynovially, intra-articularly, intraperitoneally, topically, transdermally, or by application to a mucosal surface.
  • the therapeutic agent is administered intrasynovially.
  • the therapeutic agents may also be delivered to the patient at multiple sites.
  • the multiple administrations may be rendered simultaneously or over a period of several hours. In certain cases it may be beneficial to provide a continuous flow of the therapeutic composition. Additional therapy may be administered on a periodic basis, for example, daily, weekly or monthly.
  • the therapeutic agents may be formulated with uptake or absorption enhancers to increase their efficacy.
  • enhancers include for example, salicylate, glycocholate/linoleate, glycholate, aprotinin, bacitracin, SDS caprate and the like (see, e.g., Fix et al., "Strategies for Delivery of Peptides Utilizing Absorption-Enhancing Agents," J. Pharm. Sci. 85: 1282-1285 (1996); and Oliyai and Stella, "Prodrugs of Peptides and Proteins for Improved Formulation and Delivery," Ann. Rev. Pharmacol. Toxicol. 33:521-544 (1993), which are hereby incorporated by reference in their entirety).
  • the amount of therapeutic agent in a given dosage will vary according to the size of the individual to whom the therapy is being administered as well as the characteristics of the disorder being treated.
  • single dosages may contain between about 0.01 mg and about 1000 mg of the active agent.
  • it may be appropriate to administer up to about 50 mg/day, up to about 75 mg/day, up to about 100 mg/day, up to about 150 mg/day, up to about 200 mg/day, up to about 250 mg/day, or higher amounts such as 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day, and 1000 mg/day.
  • concentrations may be administered as a single dosage form or as multiple doses. Standard dose- response studies, first in animal models and then in clinical testing, will reveal optimal dosages for particular disease states and patient populations.
  • suitable dosing and/or the effectiveness of therapy can be monitored in an individual subject by measuring lymphatic contraction rate (in pulses per minute) or lymph node volume (LNV) as surrogates for measuring the function of the lymph system.
  • LNV lymph node volume
  • a further aspect relates to a pharmaceutical composition for practicing the therapeutic methods disclosed herein.
  • the pharmaceutical composition includes a
  • the individual components of the pharmaceutical composition i.e., the sGC inhibitor or antagonist and the additional therapeutic agents can be any of those described supra.
  • the pharmaceutical composition may also contain a carrier.
  • Acceptable pharmaceutical carriers include solutions, suspensions, emulsions, excipients, powders, or stabilizers.
  • the carrier should be suitable for the desired mode of delivery, discussed supra.
  • compositions suitable for injectable use may include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Suitable carriers and/or excipients include, but are not limited to sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable carrier.
  • sterile liquids such as water and oils
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solutions, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
  • Oral dosage formulations of the pharmaceutical composition can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • suitable carriers include lubricants and inert fillers such as lactose, sucrose, or cornstarch.
  • these compounds are tableted with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, gum gragacanth, cornstarch, or gelatin; disintegrating agents such as cornstarch, potato starch, or alginic acid; a lubricant like stearic acid or magnesium stearate; and sweetening agents such as sucrose, lactose, or saccharine; and flavoring agents such as peppermint oil, oil of wintergreen, or artificial flavorings.
  • conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, gum gragacanth, cornstarch, or gelatin
  • disintegrating agents such as cornstarch, potato starch, or alginic acid
  • a lubricant like stearic acid or magnesium stearate
  • sweetening agents such as sucrose, lactose, or saccharine
  • flavoring agents such as peppermint oil, oil of wintergreen, or artificial
  • An additional aspect relates to a therapeutic system for treating an antiinflammatory condition (or inflammatory joint flare or condition associated with a decreased lymphatic pulse).
  • This therapeutic system includes a first pharmaceutical composition comprising a pharmaceutically acceptable carrier and an sGC inhibitor; and a second pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more of the (additional) therapeutic agents of the type described above.
  • Each of the first and second pharmaceutical compositions of the therapeutic system can take the forms of those described supra for the pharmaceutical composition that contains both active agents.
  • Each composition of the therapeutic system is suitable for administering directly or indirectly into a subject, including but not limited to orally, subcutaneously, intravenously, intramuscularly, parenterally, intrasynovially, intra-articularly, intraperitoneally, topically, transdermally, or by application to a mucosal surface.
  • the first and second pharmaceutical compositions may be introduced by the same route or by different routes, as needed.
  • mice The 3647 line of TNF-transgenic mice in a C57BL/6 background were originally obtained from Dr. George Kollias (Institute of Immunology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece). The TNF-Tg mice are maintained as heterozygotes, such that non-transgenic littermates are used as aged-matched wild type (WT) controls.
  • WT wild type
  • CE-MRI Contrast enhanced magnetic resonance imaging
  • CE-MRI images were followed by segmentation and quantification of knee synovial and lymph node volume.
  • ICG-NIR Indocyanine Green Near-IR
  • Lymphatic Imaging Lymphatic drainage was quantified by ICG-NIR. Indocyanine green was dissolved in distilled water and injected intradermally into the mouse footpad. ICG-NIR imaging was performed after ICG injection. Lymphatic pulsing frequency was quantified by analysis of NIR-ICG imaging of a region of interest.
  • Intravital Inmmunofluorescent Microscope of lymphatics Intravital
  • immunofluorescent microscopy was performed on draining lymphatic vessels afferent to PLN by injecting FITC conjugated anti-CDl lb, anti-Gr-1 , anti-CD19, anti-CD3, or anti-CD45.2 antibody into the footpad of TNF-Tg or wild type mice prior to imaging. Immediately prior to imaging, Texas red-conjugated dextran beads were subcutaneously injected into the footpad to mark the draining lymphatic vessel.
  • Example 1 Asymmetric Knee Flare is Associated with PLI Collapse and the
  • CE-MRJ contrast enhanced magnetic resonance imaging
  • CE-MRI imaging of an early RA patient knee experiencing arthritic flare with increased lymphatic flow confirmed the presence of an inflamed synovium, bone marrow edema in the femur and tibia, and a bright PLN (Figure 1A).
  • 3D segmentation analysis of the same patient knee showed a region of uniformly distributed inflammatory tissue (red region
  • PLN was harvested from RA patients during total knee replacement surgery and processed for histology and
  • the TNF-Tg model of chronic arthritis mimics RA in the delayed onset of disease, progression of destructive arthritis, and characteristics such as asymmetric arthritis. For these reasons, the TNF-Tg model is an ideal model for longitudinal studies investigating the progression of lymphatic dysfunction in the presence of chronic inflammation.
  • Example 3 The Nitric Oxide Receptor sGC is Found in Lymphatic Vessels of
  • lymphatic collecting vessels are comprised of an endothelial cell layer surrounded by a layer of smooth muscle cells ("SMCs"). NO molecules produced by endothelial cells diffuse to SMCs and bind to the nitric oxide receptor sGC. Following this binding, cGMP is activated in SMCs, acting on the contractile apparatus and leading to dilation of the vessel. Upon degradation of NO, the vessel contracts and the cycle repeats. While it is known that the sGC receptor, comprised of subunits alpha 1 and betal, is found in SMCs in blood vessels, its presence in SMCs surrounding the lymphatics has not been previously established.
  • SMCs smooth muscle cells
  • Pharmacological inhibition of the sGC receptor can be produced using the selective, irreversible inhibitor NS-2028.
  • An immediate visual difference was apparent between the limb given drug ( Figure 5B) and the control limb ( Figure 5A).
  • the NS-2028 treated limb appeared to have increased ICG uptake in lymphatic vessels (Figure 5C) compared to control ( Figure 5A).
  • Measurement of the lymphatic pulse showed that the pulse activity was also clearly different from control, with an increased number of doublets and triplet spikes (Figure 6A).
  • NO plays a key role in the contraction and dilation cycle of the lymphatic vessels.
  • Figures 7A-7D show that macrophages that express inducible nitric oxide synthase (iNOS) are the primary cells moving through the lymphatic vessels efferent from inflamed joints in TNF-Tg mice.
  • Figure 7E shows the absence of CD45.2 + cells in the PLN of WT mice.
  • Figure 7F shows a significant increase in Grl + /iNOS + cells in collapsed and expanded PLNs.
  • Example 6 - NS-2028 does not Induce Adverse Systemic Effects in TNF-Tg Mice
  • Example 7 Ex vivo Measurement of Lymphatic Properties
  • Lymphatic collecting vessels were isolated and cannulated from TNF-Tg mice for ex vivo analysis in the absence (Figure 9B) and presence (Figure 9C) of Ca + channel blocker BayK8644.
  • Figure 9A shows TNF-Tg popliteal collecting lymphatic vessels tied to two glass pipettes for pressure control.
  • Figures 9B-C show the raw tracing of TNF-Tg lymphatic contractions during a pressure step protocol. Input and output pressures (cmFLO, blue and red, respectively) are displayed on the top trace and are overlaid because they were changed simultaneously from 0.5 to 1, 2, 3, 5, 7, and 10 cmFLO.
  • the bottom traces plot the inner diameter ( ⁇ ) measured continuously over time.
  • lymphatics e.g., lymphatic clearance and lymphatic pulse
  • sGC inhibitors will be administered for treatment of both serum-transfer and TNF- Tg murine models of acute and chronic arthritis, respectively. Treatment is expected to accelerate lymphatic drainage of inflamed joints by increasing the number of open efferent lymphatic vessels ( Figure 5) and increasing the lymphatic pulse ( Figure 6).
  • the serum-transfer model in which the administration of sera from K/BxN mice to wild type mice results in antibody-mediated active joint inflammation similar to RA, is an acute model of arthritis.
  • wild type mice challenged with sera from K/BxN mice will be administered NS-2028 or 4,4'-((6-nitroquinoxaline-2,3-diyl)bis(azanediyl))diphenol ⁇ see Mota et al., Bioorg. Med. Chem. 23(17):5303-5310 (2015), which is hereby incorporated by reference in its entirety) prior to and 10 days following serum transfer.
  • mice will be imaged with CE-MRI and PD-US to assess synovial and lymph node inflmaation, NIR-ICG to measure lymphatic pulse and assess lymphatic function, and Micro-CT to quantify bone erosion prior to and following treatment. Histology of affected tissues (e.g., PLN, joint, and bone) will also be performed.
  • the TNF-Tg mouse model of chronic arthritis mimics RA in the delayed onset of disease, progression of destructive arthritis, and characteristics such as asymmetric arthritis.
  • TNF- Tg mice will be treated with NS-2028 or 4,4'-((6-nitroquinoxaline-2,3- diyl)bis(azanediyl))diphenol (see Mota et al., "A New Small Molecule Inhibitor of Soluble Guanylate Cyclase,” Bioorg. Med. Chem. 23(17): 5303-5310 (2015), which is hereby incorporated by reference in its entirety) prior to and following PLN collapse.
  • Drug effects on knee synovitis, lymphatic function, and bone erosion will be assessed by CE-MRI, NIR-ICG imaging, PD-US, micro-CT, and histology.
  • Arthritic flare can be induced in TNF-Tg mice using ultrasound and injection of microbubbles (see Bouta et al., "The Role of the Lymphatic System in Inflammatory-Erosive Arthritis," Semin. Cell Dev. Biol. 38:90-7 (2015), which is hereby incorporated by reference in its entirety), which leads to the loss of lymphatic pulse.
  • the sGC inhibitor will be given both prophylactically and therapeutically to determine the effect on arthritic knee flare.

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Abstract

La présente invention concerne des méthodes et des compositions permettant de traiter un érythème articulaire inflammatoire chez un sujet, un état pathologique associé à une baisse des pulsations lymphatiques, ou un état pathologique articulaire inflammatoire. Ces méthodes consistent à sélectionner un sujet présentant un érythème articulaire inflammatoire, une baisse des pulsations lymphatiques, ou un état pathologique articulaire inflammatoire ; et à administrer au sujet sélectionné un inhibiteur de guanylyl cyclase soluble (« sGC ») en quantité efficace pour traiter l'érythème articulaire inflammatoire, pour augmenter les pulsations lymphatiques, traitant ainsi l'état pathologique associé, ou pour traiter l'état pathologique articulaire inflammatoire.
PCT/US2015/049450 2014-09-10 2015-09-10 Effets d'inhibition de la guanylyl cyclase soluble sur le système vasculaire lymphatique Ceased WO2016040650A1 (fr)

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Citations (4)

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US20100152819A1 (en) * 2004-11-22 2010-06-17 Research Foundation Of State University Of New York Method for enhancing blood and lymph flow in the extremities
WO2013122855A1 (fr) * 2012-02-14 2013-08-22 University Of Rochester Procédés d'augmentation du transport lymphatique
US20130273140A1 (en) * 2007-08-24 2013-10-17 The Uab Research Foundation Controlled Release Formulations

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US4931285A (en) * 1988-04-28 1990-06-05 Alza Corporation Aqueous based pharmaceutical coating composition for dosage forms
US20100152819A1 (en) * 2004-11-22 2010-06-17 Research Foundation Of State University Of New York Method for enhancing blood and lymph flow in the extremities
US20130273140A1 (en) * 2007-08-24 2013-10-17 The Uab Research Foundation Controlled Release Formulations
WO2013122855A1 (fr) * 2012-02-14 2013-08-22 University Of Rochester Procédés d'augmentation du transport lymphatique

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GARTHWAITE, J ET AL.: "Potent and Selective Inhibition of Nitric Oxide-Sensitive Guanylyl Cyclase by 1H-[1,2,4]Oxadiazoio[4,3-a]quinoxalin-1-one.", MOLECULAR PHARMACOLOGY, vol. 48, 1995, pages 184 - 188, Retrieved from the Internet <URL:http://www.researchgate.net/profile/John_Garthwaite/publication/15655547_Potentand_selective_inhibition_of_nitric_oxide-sensitive_guanylyl_cyclase_by_1H-124oxadiazolo43-aquinoxalin-1-one/links/552e83520cf2d4950718e0fb.pdf> [retrieved on 20151028] *
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