WO2006048884A1 - Traitement therapeutique de resorption osseuse acceleree - Google Patents

Traitement therapeutique de resorption osseuse acceleree Download PDF

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Publication number
WO2006048884A1
WO2006048884A1 PCT/IL2005/001166 IL2005001166W WO2006048884A1 WO 2006048884 A1 WO2006048884 A1 WO 2006048884A1 IL 2005001166 W IL2005001166 W IL 2005001166W WO 2006048884 A1 WO2006048884 A1 WO 2006048884A1
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group
alkyl
agonist
amino
aryl
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PCT/IL2005/001166
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English (en)
Inventor
Pnina Fishman
Sara Bar Yehuda
Lea Madi
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Can-Fite Biopharma Ltd.
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Priority to JP2007539712A priority Critical patent/JP2008519029A/ja
Priority to BRPI0517639-5A priority patent/BRPI0517639A/pt
Priority to US10/564,620 priority patent/US20080051364A1/en
Priority to AU2005302090A priority patent/AU2005302090A1/en
Priority to CA002586845A priority patent/CA2586845A1/fr
Priority to EP05799989A priority patent/EP1811982A1/fr
Priority to MX2007005525A priority patent/MX2007005525A/es
Publication of WO2006048884A1 publication Critical patent/WO2006048884A1/fr
Priority to IL182988A priority patent/IL182988A0/en

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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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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

  • This invention relates to therapeutic methods for treatment or prevention of accelerated bone loss.
  • disorders in humans and other mammals involve or are associated with accelerated bone resorption.
  • Such disorders include, but are not limited to, osteoporosis, Paget's disease, peri-prosthetic bone loss or osteolysis, and hypercalcemia of malignancy.
  • the most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Because the disorders associated with bone loss are chronic conditions, it is believed that appropriate therapy will generally require chronic treatment.
  • Rheumatoid arthritis is one example of a chronic inflammatory autoimmune disease which is associated with bone loss.
  • RA affects 1% of the adult population and is characterized by hyperplasia of stromal cells and a massive infiltration of hematopoietic cells into the joints, leading to chronic synovitis and destruction of cartilage, bone, tendons and ligaments.
  • Patients with RA show a reduced bone volume and decreased bone turnover, which is further developed to osteoporosis [Perez-Edo L, et al. J. Scand J Rheumatol., 31:285- 290 (2002)].
  • This progressive joint damage results in functional decline and disability [Harris ED. N. Eng.l J. Med., 322:1277-1289 (1990)].
  • About 80% of the affected population becomes disabled within 20 years of symptom onset [Paulos CM, et al. Adv. Drug. Deliv. Rev., 56: 1205-1217 (2004)].
  • RANKL is highly expressed on outer plasma membrane of osteoblasts, stromal cells, synovial fibroblasts and T cells in arthritic joints [Kwan Tat S, et al. Cytokine Growth. Factor Rev., 5:49-60 (2004); Kotake S, et al. Arthritis. Rheum., 44:1003-1012 (2001)]. It binds to its receptor RANK, which is present on the osteoclasts progenitors, evoking downstream PI3 K-PKB signaling pathway, leading to the activation of the transcription factor NF-KB [Udagawa N, et al. Arthritis. Res., 4:281-289. (2002); Gingery A, et al. J. Cell. Biochem., 89: 165-179 (2003)].
  • adenosine plays an important role in limiting inflammation, mainly by prevention pro-inflammatory cytokine production such as TNF- ⁇ , IL-I and IL-6 [Cronstein, B.N. J. Appl. Physiol. 76:5- 13 (1994); Eigler, A., et al. Scand. J. Immunol, 45: 132-139 (1997); Mabley, J., et al. Eur. J. Pharmacol. 466:323-329 (2003)].
  • Adenosine which is released into the extra cellular environment from activated or metabolically stimulated cells, binds to selective G-protein-associated membrane receptors, designated A 1 , A 2A , A 2B , and A 3 [Stiles, G.L., Clin. Res. 38:10-18 (1990)].
  • the anti-inflammatory effect of adenosine was found to be mediated via the A 3 AR [Szabo, C, et al. Br. J. Pharmacol. 125:379-387 (1998)].
  • IB-MECA is efficacious in preventing the clinical and pathological manifestations of arthritis in different experimental animal models which included Adjuvant Induced Arthritis (AJA), collagen induced arthritis (CIA) and thropomyosine induced arthritis.
  • AJA Adjuvant Induced Arthritis
  • CIA collagen induced arthritis
  • thropomyosine induced arthritis The mechanism of action entailed down-regulation of NF-kB, TNF- ⁇ and MIP- l ⁇ [Baharav E., et al. J. Rhematol. Accepted (2004)].
  • the present invention is based on the surprising finding that the highly selective A 3 AR agonist, IB-MECA, prevents bone loss in an Adjuvant Induced
  • AIA Arthritis
  • the present invention provides a method for the treatment of accelerated bone resorption in a mammal subject comprising administering to said subject in need of said treatment an amount of an A 3 adenosine receptor agonist (A 3 AR agonist), the amount being effective to inhibit bone resorption.
  • a 3 AR agonist A 3 adenosine receptor agonist
  • treatment denotes curative as well as prophylactic treatment.
  • treatment includes inhibition of accelerated bone resorption and of the development of osteolytic lesions.
  • treatment of bone resorption encompass amelioration of undesired symptoms associated with bone resorption (e.g. pain, bone fractures, spinal cord compression, and hypercalcemia), prevention of the manifestation of such symptoms before they occur, slowing down or prevention of irreversible damage caused by chronic stages of a disease associated with bone loss (e.g. preventing the development of osteolytic lesions and fractions), lessening the severity of diseases associated with bone resorption, improvement of bone recovery, prevention of bone resorption from developing, prevention of bone tissue death, as well as any improvement in the well being of the patients.
  • an improvement may be manifested by one or more of the following: increase in bone mass, relief of pain associated with bone resorption, reduction in bone fractioning and others.
  • treatment may also include a combination of two or more of the above.
  • accelerated bone resorption which may be used interchangeably with the terms “accelerated bone loss”, “accelerated bone destruction” and " Osteoclastic bone” in the context of the present invention refers to any disease, disorder or pathological condition which involves the development of osteoclastic bone and may be either as a result of a metabolic bone disease, from accelerated metabolic processes induced by inflammation or by any other pathological condition.
  • diseases involved with bone resorption include osteoporosis, Paget's disease, peri-prosthetic bone loss, osteonecrosis (death or destruction of bone tissue due to trauma, loss of blood supply or disease), myeloma bone disease, osteolysis, and hypercalcemia of malignancy.
  • a 3 adenosine receptor agonist in the context of the present invention refers to any compound capable of specifically binding to the A 3 adenosine receptor ("A 3 AR"), thereby fully or partially activating said receptor.
  • the A 3 AR agonist is thus a compound that exerts its prime effect through the binding and activation of the A 3 AR. Preferred embodiments OfA 3 AR agonists are provided hereinafter.
  • the “amount” (herein also termed the "effective amount”) OfA 3 AR agonist in the context of the present invention refers to an amount effective to provide protection of a mammal from bone resorption as well as from the development of diseases associated with bone resorption.
  • An amount being effective to provide the desired protection can be readily determined, in accordance with the invention, by administering to a plurality of tested subjects various amounts of the A 3 AR agonist and then plotting the physiological response (for example an integrated "SS index " combining several of the therapeutically beneficial effects) as a function of the amount.
  • the effective amount may also be determined, at times, through experiments performed in appropriate animal models and then extrapolating to human beings using one of a plurality of conversion methods; or by measuring the plasma concentration or the area under the curve (AUC) of the plasma concentration over time and calculating the effective dose so as to yield a comparable plasma concentration or .AUC.
  • the effective amount may depend on a variety of factors such as mode of administration (for example, oral administration may require a higher dose to achieve a given plasma level or AUC than an intravenous administration); the age, weight, body surface area, gender, health condition and genetic factors of the subject; other administered drugs; etc.
  • dosages are indicated in weight/Kg, meaning weight of administered A 3 AR agonist per kilogram of body weight of the treated subject in each administration.
  • mg/Kg and microgram/Kg denote, respectively, milligrams of administered agent and micrograms of administered agent per kilogram of body weight of the treated subject.
  • the effective amount is typically less than about 1000 and preferably less than about 500 microgram/Kg.
  • a typical dose would be in the range of about 1 microgram/Kg to about 200 microgram/Kg, with a preferred dose being in the range of about 5 microgram/Kg to about 150 microgram/Kg.
  • the corresponding effective amount in a human will be a human equivalent amount to that observed in mice, which may be determined in a manner as explained bellow.
  • human equivalent refers to the dose that produces in human the same effect as featured when a dose of 0.001-1 mg/Kg of an A 3 AR agonist is administered to a mouse or a rat. As known, this dose depends and may be determined on the basis of a number of parameters such as body mass, body surface area, absorption rate of the active agent, clearance rate of the agent, rate of metabolism and others.
  • the human equivalent may be calculated based on a number of conversion criteria as explained bellow; or may be a dose such that either the plasma level will be similar to that in a mouse following administration at a dose as specified above; or a dose that yields a total exposure (namely area under the curve, 'AUC, of the plasma level of said agent as a function of time) that is similar to that in mice at the specified dose range.
  • Rat (150g) to Man (70 Kg) is 1/7 the rat dose. This means that, for example, 0.001-1 mg/Kg in rats equals to about 0.14-140 microgram/Kg in humans. Assuming an average human weight of 70 Kg, this would translate into an absolute dosage for humans of about 0.01 Xo about 10 mg.
  • Another alternative for conversion is by setting the dose to yield the same plasma level or AUC as that achieved following administration to an animal. For example, based on measurement made in mice following oral administration of IB-MECA and based on such measurements made in humans in a clinical study in which IB-MECA was given to healthy male volunteers it can be concluded that a dose of 1 microgram/Kg - 1,000 microgram/KG in mice is equivalent to a human dose of about 0.14 - 140 microgram/Kg, namely a total dose for a 70 Kg individual of O.Ol - lO mg. Based on the above conversion methods, the preferred dosage range for two specific A 3 AR agonist, e.g.
  • IB-MECA and Cl-IB-MECA would be less than 4 mg, typically within the range of about 0.01 to about 2 mg (about 0.14 - 28 micrograms/Kg, respectively) and desirably within the range of about 0.1 to 1.5 mg (about 1.4 - 21 micrograms/Kg, respectively).
  • This dose may be administered once, twice or, at times, several times a day.
  • compositions for the treatment of accelerated bone resorption comprising as the active ingredient an amount of an A 3 AR agonist and a pharmaceutically acceptable carrier, the amount being effective to inhibit bone resorption in a subject in need of said treatment.
  • pharmaceutically acceptable carrier in the context of the present invention denotes any one of inert, non-toxic materials, which do not react with the A 3 AR agonist and which can be added to formulations as diluents, carriers or to give form or consistency to the formulation.
  • the carrier also includes substances for providing the formulation with stability, sterility and isotonicity (e.g.
  • antimicrobial preservatives for preventing the action of microorganisms (e.g. antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like), for providing the formulation with an edible flavor or with a color etc.
  • microorganisms e.g. antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like
  • the carrier may also at times have the effect of the improving the delivery or penetration of the A 3 AR agonist to the target tissue, for improving the stability of the A 3 AR agonist, for slowing clearance rates, for imparting slow release properties, for reducing undesired side effects etc.
  • the present invention encompasses the use of an A 3 AR agonist for the preparation of a pharmaceutical composition for the treatment of accelerated bone resorption.
  • Figs. 1A-1C include graphs showing the clinical score (Fig. IA) and paw thickness (Fig. IB) after treatment with IB-MECA of AIA rats, as well as pictures (Fig. 1C) demonstrating the severe redness and swelling of the entire paw in the control group (left picture), in comparison to a representative paw in the IB-MECA treated group, which appears completely normal (right picture).
  • Figs. 2A-2C include a bar graph providing inflammation score (Fig. 2A) as well as histological cross sections (x20 and x40) (Fig. 2B) showing the change in inflammation in the joints of IB-MECA treated rates compared to control rats.
  • Figs. 3A-3B include a bar graph of fibrosis score (Fig. 3A) as well as histological cross sections (Fig. 3B), showing the change in the synovium in IB-MECA treated rates, compared to control rats.
  • Figs. 4A-4B include a bar graph of pannus score (Fig. 4A) and histological cross sections (Fig. 4B) showing the change in the pannus tissue in the articular space of IB-MECA treated rats, compared to control rates
  • Figs. 5A-5B include a bar graph of cartilage destruction score (Fig. 5A) as well as histological cross sections (Fig. 5B) showing the change in the cartilage in IB-MECA treated rats, compared to control rats.
  • Figs. 6A-6B include a bar graph of osteoclasts score (Fig. 6A) as well as histological cross sections (Fig. 6B) showing the change in the appearance of osteoclasts in IB-MECA treated rats, comparted to the control rats.
  • Figs. 7A-7B include a bar graph of bone destruction score (Fig. 7A) as well as histological cross sections (Fig. 7B) showing the change in bone mass in IB-MECA treated rats, compared to the control rats.
  • Figs. 8A-8B include a bar graph of osteoblasts score (Fig. 8A) as well as histological cross sections (Fig. 8B) showing the change in osteoblasts population in IB-MECA treated rats, compared to the control rats.
  • Figs. 9A-9B include a bar graph of new bone formation score (Fig. 9A) as well as histological cross sections (Fig. 9B) showing new bone formation in IB- MECA treated rats, compared to untreated group.
  • Figs. 10A-10D show the effect of IB-MECA treatment on the expression of A3AR (Fig. 10A) and additional key regulatory proteins in paw extracts, including RANKL (Fig. 10B), PBK; PKB/Akt; IKK ⁇ , ⁇ ; NF- ⁇ B and TNF- ⁇ (Fig. 10C) as well as white blood (WB) analysis of the apoptotic enzyme caspase-3 (Fig. 10D).
  • RANKL Fig. 10B
  • PBK PBK
  • PKB/Akt IKK ⁇ , ⁇
  • NF- ⁇ B and TNF- ⁇ Fig. 10C
  • WB white blood
  • osteogenesis involves three main steps: production of production of the extracellular organic matrix (osteoid); mineralization of the matrix to form bone; and bone remodeling by resorption and reformation.
  • the cellular activities of osteoblasts, osteocytes, and osteoclasts are essential to the process. Osteoblasts synthesize the collagenous precursors of bone matrix and also regulate its mineralization. As the process of bone formation progresses, the osteoblasts come to lie in tiny spaces (lacunae) within the surrounding mineralized matrix and are then called osteocytes. 1 Fo meet the requirements of skeletal growth and mechanical function, bone undergoes dynamic remodeling by a coupled process of bone resorption by osteoclasts and reformation by osteoblasts.
  • osteoclasts and osteoclastlike cells have been identified as important effector cells in mediating inflammation-induced bone loss in, for example, inflammatory arthritis (e.g. rheumatoid arthritis and psoriatic arthritis).
  • the present invention aims for the providence of a method for inhibiting accelerated, bone resorption and thereby curing or preventing the consequences of abnormal bone loss.
  • a method for the treatment of accelerated bone resorption in a mammal subject comprises administering to said subject in need of said treatment an amount of an
  • a 3 adenosine receptor agonist (A 3 AR agonist), the amount being effective to inhibit bone resorption.
  • a 3 AR agonist is preferably a compound that exerts its prime effect through the binding and activation of the A 3 AR.
  • an A 3 AR agonist has a binding affinity (K ; ) to the humaji adenosine A 3 receptor in the range of less than 10O nM, typically less than 5O nM, preferably less than 20 nM, preferably less than 10 nM and ideally less than 5 nM.
  • K ; to the human A 3 R of less than 2 nM and desirably less than 1 nM.
  • a 3 AR agonists can also interact with and activate other receptors with lower affinities (namely a higher Ki).
  • a compound will be considered an A 3 AR agonist in the context of the invention (namely a compound that exerts its prime effect through the binding and activation A 3 AR) if its affinity to the A 3 AR is at least 3 times (i.e. its Ki to the A 3 AR is at least 3 times lower), preferably 10 times, desirably 20 times and most preferably at least 50 times larger than the affinity to any other of the adenosine receptors (i.e. A 1 , A 2a and A 2b ).
  • the affinity of an A 3 AR agonist to the human A 3 AR as well as its relative affinity to the other human adenosine receptors can be determined by a number of assays, such as a binding assay.
  • assays include providing membranes containing a receptor and measuring the ability of the A 3 AJL agonist to displace a bound radioactive agonist; utilizing cells that display the respective human adenosine receptor and measuring, in a functional assay, the ability of the A 3 AR agonist to activate or deactivate, as the case may be, downstream signaling events such as the effect on adenylate cyclase measured- through increase or decrease of the cAMP level; etc.
  • an A 3 AR agonist is thus preferably administered at a dose such that the blood level is such so that essentially only the A 3 AR will be activated.
  • the A 3 AR agonist is a compound that exerts its prime effect through the binding and activation A 3 AR and is a purine derivative falling within the scope of the general formula (I) and physiologically acceptable salts of said compound:
  • R 1 represents an alkyl, hydroxyalkyl, carboxya.]kyl or cyanoalkyl or a group of the following general formula (II):
  • Y represents oxygen, sulfur or CH 2 ;
  • X 1 represents H, alkyl, R 3 R 13 NC( ⁇ O)- or HOR 0 -, wherein
  • R a and R b may be the same or different and are selected from the group consisting of hydrogen, alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl, and cycloalkyl or are joined together to form a heterocyclic ring containing two to five cart>on atoms; and
  • R c is selected from the group consisting of alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl, and cycloalkyl;
  • X 2 is H, hydroxyl, alkylamino, alkylamido or hydroxyalkyl
  • R' and R" represent independently an alkyl group
  • R 2 is selected from the group consisting of hydrogen, halo, alkylether, amino, hydrazido, alkylamino, alkoxy, thioalkoxy, pyridylthio, alkenyl; alkynyl, thio, and alkylthio; and
  • - R 3 is a group of the formula -NR 4 R 5 wherein
  • R 4 is a hydrogen atom or a group selected from alkyl, substituted alkyl or aryl-NH-C(Z)-, with Z being O, S, or NR a with R a having the above meanings; wherein when R 4 is hydrogen than
  • R 5 is selected from the group consisting of R- and S-1-phenylethyl, benzyl, phenylethyl or anilide groups unsubstituted or substituted in one or more positions with a substituent selected from the group consisting of alkyl, amino, halo, haloalkyl, nitro, hydroxyl, acetoamido, alkoxy, and sulfonic acid or a salt thereof; benzodioxanemethyl, furaryl, L-propylalanyl- aminobenzyl, ⁇ -alanylamino- benzyl, T-BOC- ⁇ -alanylaminobenzyl, phenylamino, carbamoyl, phenoxy or cycloalkyl; or R 5 is a group of the following formula:
  • R 5 is selected from the group consisting of heteroaryl-NR a -C(Z)-, heteroaryl-C(Z)-, alkaryl-NR a -C(Z>, alkaryl- C(Z)-, aryl-NR-C(Z)- and aryl-C(Z)-; Z representing an oxygen, sulfor or amine; or a physiologically acceptable salt of the above compound.
  • the A 3 RAg is a nucleoside derivative of the general formula (IV): wherein X x , R 2 and R 4 are as defined above, and physiologically acceptable salts of said compound.
  • non-cyclic carbohydrate groups e.g. alkyl, alkenyl, alkynyl, alkoxy, aralkyl, alkaryl, alkylamine, etc
  • the non-cyclic carbohydrate groups are either branched or unbranched, preferably containing from one or two to twelve carbon atoms.
  • alkyl denotes any saturated carbohydrate, either linear or branched.
  • lower alkyl denotes a saturated carbohydrate (linear or branched) comprising from 1 to about 10 carbon atoms in the backbone.
  • alkenyF and "a ⁇ kynyF as used herein denote refer to linear or branched carbohydrates wherein at least two adjacent carbon atoms are connected via a double or triple bond, respectively. Accordingly, the terms “lower alkenyF and “lower alkynyF refer to linear or branched carbohydrates comprising from 2 to
  • non-toxic acid addition salts which are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid. The resulting acid addition salts are those which retain the biological effectiveness and qualitative properties of the free bases and which are not toxic or otherwise undesirable.
  • Examples include, inter alia, acids derived from mineral acids, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, rnetaphosphoric and the like.
  • Organic acids include, inter alia, tartaric, acetic, propionic, citric, malic, malonic, lactic, fumaric, benzoic, cinnamic, mandelic, glycolic, gluconic, pyruvic, succinic salicylic and arylsulphonic, e.g. p-toluenesulphonic, acids.
  • a 3 AR agonist which may be employed according to general formula (IV) of the present invention include, without being limited thereto, N 6 -2- (4-aminophenyl)ethyladenosine (APNEA), N 6 -(4-amino-3-iodobenzyl) adenosine- 5'-(N-methyluronamide) (AB-MECA), N 6 -(3-iodobenzyl)-adenosine-5'- N- methyluronamide (IB-MECA) and 2-chloro-N 6 -(3-iodobenzyl)- adenosine- 5 '-N- methyluronamide (Cl-IB-MECA).
  • APIA N 6 -2- (4-aminophenyl)ethyladenosine
  • AB-MECA N 6 -(4-amino-3-iodobenzyl) adenosine- 5'-(N-methyluron
  • a preferred A 3 AR agonist according to the invention is IB-MECA.
  • the A 3 AR agonist may be an oxide derivative of adenosine, such as N 6 -benzyladenosine-5'-N-alkyluronamide-
  • N ⁇ oxide or N ⁇ benzyladenosine-S'-N-dialkyluronarnide-lN ⁇ -oxide wherein the 2-purine position may be substituted with an alkoxy, amino, alkenyl, alkynyl or halogen.
  • Accelerated bone loss may be due to an accelerated metabolic process, as a result of a bone disease, or induced by inflammation. As appreciated by those versed in the art, long-term inflammation can have the effect of removing calcium from the bones, weakening and shrinking them. Inflammation-mediated bone loss occurs in various diseases such as periodontal disease, osteo- and rheumatoid arthritis and some forms of osteoporosis.
  • the invention concerns treatment of accelerated bone resorption induced by inflammation.
  • Axcording to a preferred embodiment, the method of the invention is for the accelerated bone resorption resulting from inflammatory arthritis.
  • the invention also concerns pharmaceutical compositions for the treatment of accelerated bone resorption as detailed hereinbefore, the composition comprising as the active ingredient an amount of an A 3 AR agonist and a pharmaceutically acceptable carrier, the amount being effective to inhibit bone resorption in a subject in need of said treatment.
  • composition of the present invention is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners.
  • the choice of carrier will be determined in part by the particular active ingredient, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable pharmaceutical compositions of the present invention.
  • the pharmaceutical composition is in a form suitable for oral administration.
  • carriers suitable for oral administration include (a) liquid solutions, where an effective amount of the A 3 AR agonist is dissolved in diluents, such as water, saline, natural juices, alcohols, syrups, etc.; (b) capsules (e.g.
  • the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers), tablets, lozenges (wherein the A 3 AR agonist is in a flavor, such as sucrose or the A 3 AR agonist is in an inert base, such as gelatin and glycerin), and troch.es, each containing a predetermined amount of A 3 AR agonist as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; (e) suitable emulsions; (f) liposome formulation; and others.
  • the invention concerns the use OfA 3 AR agonist for the preparation of a pharmaceutical composition for the treatment of accelerated bone resorption.
  • the invention will now be exemplified in the following description of experiments that were carried out in accordance with the invention. It is to be understood that these examples are intended to be in the nature of illustration rather than of limitation. Obviously, many modifications and variations of these examples are possible in light of the above teaching. It is therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise, in a myriad of possible ways, than as specifically described hereinbelow.
  • Incomplete Freund's adjuvant was purchased from Sigma and heat killed Mycobacterium tuberculosis H37Ra, from Difco (Detroit, USA). Rabbit polyclonal antibodies against rat A 3 AR, and the signaling proteins
  • IKK, TNF- ⁇ , GSK-3 ⁇ , caspase-3 and phospho-specific PKB/Akt, RANKL were purchased from Santa Cruz Biotechnology Inc., Ca, USA.
  • the NF- ⁇ B antibody was purchased from cell signaling.
  • SC subcutaneously
  • Drugs were orally administered by gavage, twice daily.
  • the positive control received vehicle only (DMSO in a dilution corresponding to that of the drug) while the treatment groups received 10 ⁇ g/kg of IB-MECA. Treatment was initiated on day 14 after vaccination.
  • the animals were inspected every second day for clinical arthritis.
  • the scoring system ranged from 0-4 of each limb: 0- no arthritis; 1- redness or swelling of one toe/finger joint; 2- redness and swelling of more than one toe/finger joints, 3 -the ankle and tarsal-metatarsal joints involvement. 4- entire paw redness or swelling.
  • the inflammatory intensity was also determined in accordance with the increase in the rat hind paw's diameter, measured by caliper (Mitotoyo, Tokyo, Japan).
  • Histological score The foot, knee and hip region of both vehicle and CFlOl treated animals were collected and fixed in 10% buffered formalin and decalcified in hydrochloric acid (Calci-Clear Rapid) (Pational Diagnostics, Gr, USA) for 24 h. The specimens were then processed for paraffme embedding, histologic 4- ⁇ m sections were cut and stained with hematoxylin and eosin. The sections were assessed by a pathologist blinded to the treatment protocols, and each joint was scored separately.
  • the histology score was assessed as follows: A score of 0 to 4 for the extent of inflammatory cells' infiltration to was used according to the followed: 0- Normal; 1 - minimal inflammatory infiltration; 2 - mild infiltration; 3 - moderate infiltration; 4 - marked infiltration.
  • the score was graded 0-4: 0-normal; 1 -minimal loss of cortical bone at a few sites; Z- mild loss of cortical trabecular bone; 3- moderate loss of bone at many sites; 4- marked loss of bone at many sites; 5 -marked loss of bone at many sites with fragmenting and full thickness penetration of inflammatory process or pannus into the cortical bone.
  • the mean of all the histological parameter scores were designated "Histology Score".
  • the hind paws were dissected above the ankle joint.
  • the bony tissue was broken into pieces broken, snap frozen in liquid nitrogen and stored at -80 0 C until use.
  • the paw tissues were added to (4ml/g tissue) RIPA extraction buffer containg 150 mM NaCl, 50 mM Tris, 1% NP40, 0.5% Deoxycholate and 0.1% SDS. Tissues were homogenized on ice with a polytron, centrifuged and the supernatans were subjected to Western Blot analysis
  • Figure IA The IB-MECA treatmeat significantly decreased the paw edema. Also, IB-MECA treatment resulted in a 35% ⁇ 1.2 inhibition in the paw thickness (Figure IB).
  • Figure 1C is a picture demonstrating the severe redness and swelling of the entire paw in the control group, in comparison to a representative paw in the IB-MECA treated group, which appears completely normal (right).

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Abstract

L'invention concerne l'utilisation d'un agoniste du récepteur d'adénosine A3 (agoniste de A3AR) pour le traitement de la résorption osseuse accélérée, plus particulièrement de la résorption osseuse induite par une inflammation. Plus spécifiquement, l'invention concerne un procédé et une composition pharmaceutique pour le traitement de cet état pathologique, l'agoniste de A3AR étant formulé en tant que composition pharmaceutique administrée à un sujet souffrant de résorption osseuse accélérée. L'invention concerne également l'utilisation de l'agoniste de A3AR dans la préparation de cette composition pharmaceutique.
PCT/IL2005/001166 2004-11-08 2005-11-08 Traitement therapeutique de resorption osseuse acceleree WO2006048884A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
JP2007539712A JP2008519029A (ja) 2004-11-08 2005-11-08 加速骨吸収の治療的処置
BRPI0517639-5A BRPI0517639A (pt) 2004-11-08 2005-11-08 método para o tratamento de ressorção óssea acelerada, composição farmacêutica, e, uso de um agonista de a3ar
US10/564,620 US20080051364A1 (en) 2004-11-08 2005-11-08 Therapeutic Treatment of Accelerated Bone Resorption
AU2005302090A AU2005302090A1 (en) 2004-11-08 2005-11-08 Therapeutic treatment of accelerated bone resorption
CA002586845A CA2586845A1 (fr) 2004-11-08 2005-11-08 Traitement therapeutique de resorption osseuse acceleree
EP05799989A EP1811982A1 (fr) 2004-11-08 2005-11-08 Traitement therapeutique de resorption osseuse acceleree
MX2007005525A MX2007005525A (es) 2004-11-08 2005-11-08 Tratamiento terapeutico de resorcion ose acelerada.
IL182988A IL182988A0 (en) 2004-11-08 2007-05-03 Therapeutic treatment of accelerated bone resorption

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US62556404P 2004-11-08 2004-11-08
US60/625,564 2004-11-08

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AU (1) AU2005302090A1 (fr)
BR (1) BRPI0517639A (fr)
CA (1) CA2586845A1 (fr)
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1959939A1 (fr) * 2005-11-30 2008-08-27 Can-Fite Biopharma Ltd. Utilisation de l'agoniste des recepteurs de l'adenosine a3 dans le traitement de l'osteoarthrite
WO2009061516A1 (fr) * 2007-11-08 2009-05-14 New York University School Of Medicine Implants médicaux contenant des agonistes du récepteur de l'adénosine et procédés pour inhiber un relâchement d'implant médical
US9073960B2 (en) 2011-12-22 2015-07-07 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9102698B2 (en) 2007-03-14 2015-08-11 Can-Fite Biopharma Ltd. Process for the synthesis of IB-MECA
US9441007B2 (en) 2012-03-21 2016-09-13 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof

Families Citing this family (1)

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KR20120022919A (ko) * 2009-05-17 2012-03-12 캔-파이트 바이오파마 리미티드 안압의 감소를 위한 ａ3 아데노신 수용체 작동제

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WO2000072799A2 (fr) * 1999-05-27 2000-12-07 The University Of Virginia Patent Foundation Methode et compositions permettant de traiter la reponse inflammatoire
WO2001019360A2 (fr) * 1999-09-10 2001-03-22 Can-Fite Biopharma Ltd. Compositions pharmaceutiques contenant un antagoniste ou un agoniste de recepteur d'adenosine
WO2004045627A1 (fr) * 2002-11-19 2004-06-03 Can-Fite Biopharma Ltd. Agonistes a3ar utilises dans le traitement de l'arthrite inflammatoire
WO2004078184A1 (fr) * 2003-03-07 2004-09-16 Cambridge Biotechnology Ltd Utilisation d'agonistes de recepteur d'adenosine en therapie
WO2005084653A2 (fr) * 2004-03-05 2005-09-15 Cambridge Biotechnology Limited Composes therapeutiques

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2000072799A2 (fr) * 1999-05-27 2000-12-07 The University Of Virginia Patent Foundation Methode et compositions permettant de traiter la reponse inflammatoire
WO2001019360A2 (fr) * 1999-09-10 2001-03-22 Can-Fite Biopharma Ltd. Compositions pharmaceutiques contenant un antagoniste ou un agoniste de recepteur d'adenosine
WO2004045627A1 (fr) * 2002-11-19 2004-06-03 Can-Fite Biopharma Ltd. Agonistes a3ar utilises dans le traitement de l'arthrite inflammatoire
WO2004078184A1 (fr) * 2003-03-07 2004-09-16 Cambridge Biotechnology Ltd Utilisation d'agonistes de recepteur d'adenosine en therapie
WO2005084653A2 (fr) * 2004-03-05 2005-09-15 Cambridge Biotechnology Limited Composes therapeutiques

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1959939A1 (fr) * 2005-11-30 2008-08-27 Can-Fite Biopharma Ltd. Utilisation de l'agoniste des recepteurs de l'adenosine a3 dans le traitement de l'osteoarthrite
AU2006321165B2 (en) * 2005-11-30 2010-04-22 Can-Fite Biopharma Ltd. Use of A3 adenosine receptor agonist in osteoarthritis treatment
EP1959939B1 (fr) * 2005-11-30 2012-01-11 Can-Fite Biopharma Ltd. Utilisation de l'agoniste des recepteurs de l'adenosine a3 dans le traitement de l'osteoarthrite
US10265337B2 (en) 2005-11-30 2019-04-23 Can-Fite Biopharma Ltd. Use of A3 adenosine receptor agonist in osteoarthritis treatment
US9102698B2 (en) 2007-03-14 2015-08-11 Can-Fite Biopharma Ltd. Process for the synthesis of IB-MECA
WO2009061516A1 (fr) * 2007-11-08 2009-05-14 New York University School Of Medicine Implants médicaux contenant des agonistes du récepteur de l'adénosine et procédés pour inhiber un relâchement d'implant médical
US9073960B2 (en) 2011-12-22 2015-07-07 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US10464965B2 (en) 2011-12-22 2019-11-05 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US11021509B2 (en) 2011-12-22 2021-06-01 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9441007B2 (en) 2012-03-21 2016-09-13 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US10485815B2 (en) 2012-03-21 2019-11-26 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof

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CN101072554A (zh) 2007-11-14
CA2586845A1 (fr) 2006-05-11
JP2008519029A (ja) 2008-06-05
AU2005302090A1 (en) 2006-05-11
BRPI0517639A (pt) 2008-10-14
EP1811982A1 (fr) 2007-08-01
MX2007005525A (es) 2007-07-05

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