WO2001034566A2 - Inhibiteurs de la protease - Google Patents
Inhibiteurs de la protease Download PDFInfo
- Publication number
- WO2001034566A2 WO2001034566A2 PCT/US2000/030682 US0030682W WO0134566A2 WO 2001034566 A2 WO2001034566 A2 WO 2001034566A2 US 0030682 W US0030682 W US 0030682W WO 0134566 A2 WO0134566 A2 WO 0134566A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- disease
- formula
- cathepsin
- protease
- Prior art date
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- RADGOBKLTHEUQO-UHFFFAOYSA-N ruthenium(4+) Chemical compound [Ru+4] RADGOBKLTHEUQO-UHFFFAOYSA-N 0.000 description 1
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- IHQKEDIOMGYHEB-UHFFFAOYSA-M sodium dimethylarsinate Chemical compound [Na+].C[As](C)([O-])=O IHQKEDIOMGYHEB-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P33/10—Anthelmintics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention relates to a novel deuterated 4-am ⁇ no-azepan-3-one protease inhibitor.
- This compound is particularly an inhibitor of cysteine and senne proteases, more particularly an inhibitor of cysteine proteases.
- the compound of this invention even more particularly inhibits cysteine proteases of the papain superfamily, and yet more particularly cysteine proteases of the cathepsin family.
- this invention relates to a compound which inhibits cathepsin K.
- Such compound is particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthntis
- Cathepsin K is a member of the family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and charactenzed. Bossard, M. J., et al., (1996) J Biol Chem.
- Cathepsin K has been vanously denoted as cathepsin O, cathepsin X or cathepsin 02 in the literature.
- the designation cathepsin K is considered to be the more appropnate one (name assigned by Nomenclature Committee of the International Union of Biochemistry and Molecular Biology)
- Cathepsins of the papam superfamily of cysteine proteases function m the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease.
- cathepsins have been implicated in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as m schistosomiasis malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like.
- WO 94/04172 published on March 3, 1994
- references cited therein See also European Patent Application EP 0 603 873 Al, and references cited therein.
- Two bacterial cysteine proteases from P. gingivalhs, called gingipams have been implicated in the pathogenesis of gingivitis Potempa, J , et al. (1994) Perspectives in Drug Discovery and Design, 2, 445- 458.
- Bone is composed of a protein matrix in which spmdle- or plate-shaped crystals of hydroxyapatite are incorporated Type I Collagen represents the major structural protein of bone compnsing approximately 90% of the structural protein The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcm, proteoglycans, osteopontin, osteonectin, thrombospondm, fibronectin, and bone sialoprotem. Skeletal bone undergoes remodeling at discrete foci throughout life These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement
- Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
- the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface
- cathepsm K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
- Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthntic synovium
- selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matnx degradation, including, but not limited to, osteoarthntis and rheumatoid arthntis.
- Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix
- selective inhibition of cathepsm K may also be useful for treating certain neoplastic diseases
- a certain novel deuterated compound is a protease inhibitor, most particularly an inhibitor of cathepsin K, and that this compound is useful for treating diseases charactenzed by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis
- An object of the present invention is to provide a deuterated 4-am ⁇ no-azepan-3-one protease inhibitor, particularly an inhibitor of cysteine and serine proteases More particularly, the present invention relates to such a compound which inhibits cysteine proteases, and yet more particularly cysteine proteases of the papain superfamily Preferably, this invention relates to such a compound which inhibits cysteine proteases of the cathepsin family and most preferably, a compound which inhibits cathepsin K The compound of the present invention is useful for treating diseases which may be therapeutically modified by altering the activity of such proteases
- this invention provides a compound, 3- methylbenzofuran-2-carboxyl ⁇ c acid ⁇ (S)-3-methyl- 1 -[(2,2',4-tn practitionero)-3-oxo- 1 -( 1 -oxy- pynd ⁇ ne-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl ⁇ am ⁇ de, according to Formula I
- this invention provides a pharmaceutical composition compnsmg a compound according to Formula I and a pharmaceutically acceptable carrier
- this invention provides a method of treating diseases m which the disease pathology may be therapeutically modified by inhibiting proteases, such as cysteine and serine proteases
- the method includes treating diseases by inhibiting cysteine proteases, and particularly cysteine proteases of the papain superfamily More particularly, the inhibition of cysteine proteases of the cathepsin family, such as cathepsin K is descnbed
- the compound of this invention is especially useful for treating diseases characterized by bone loss, such as osteoporosis, and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
- the present invention provides a compound, 3-methylbenzofuran-2-carboxylic acid ⁇ (S)-3-methyl- 1 -[(2,2',4-trideuterio)-3-oxo- 1 -( 1 -oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl ⁇ amide, of Formula (I):
- the present invention includes all hydrates, solvates, complexes, polymorphs and prodrugs of the compound of Formula (I).
- Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula (I) in vivo.
- Prodrugs of the compound of the present invention include ketone derivatives, specifically ketals or hemiketals.
- inventive compound may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
- each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
- the 7 membered ring compound of the present invention is configurationally more stable at the carbon center alpha to the ketone.
- m- CPBA means .wet ⁇ -chloroperoxybenzoic acid
- Boc means terf-butoxycarbonyl
- EDC means l-(3-d ⁇ methylammopropyl)-3-ethylcarbodnm ⁇ de hydrochlonde
- DMSO means methyl sulfoxide
- TEA means tnethylamine
- Epoxidation of azepme 3 may be effected with standard oxidizing agents common to the art such as -CPBA to provide epoxide 4
- Nucleophilic epoxide nng opening of 4 may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown)
- Reagents and Conditions a.) NaH, 5-bromo- 1 -pentene, DMF; b.) bis(t ⁇ cyclohexylphosphme)benzyhdine ruthenium (IV) dichloride, CH 2 C1 2 : c.) /w-CPBA, CH 2 C1 2 ; d.) NaN,, CH,OH, H 2 0, NH 4 C1; e.) 1 ,3-propanedithiol, TEA, methanol; f.) N-Boc-leucine, EDC, CH 2 C1 2 ; g.) 10% Pd/C, H 2 ; h.) 2-pyridinesulphonyl chlo ⁇ de-N-oxide.
- the intermediate azido alcohol may be reduced to the ammo alcohol 5 under conditions common to the art such as 1 ,3-propanedithiol and tnethylamme m methanol or with t ⁇ phenylphosphine in tetrahydrofuran and water.
- Acylation of 5 may be effected with an acid such as N-Boc-leucine in the presence of a coupling agent such as EDC Removal of the benzyl oxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/C provides the amine 6
- a coupling agent such as EDC
- EDC electrospray Desorption
- benzyl oxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/C
- Coupling of 7 with 3-methylbenzofuran-2-carboxyhc acid may be effected with a coupling agent such as EDC to provide intermediate alcohol 8.
- Alcohol 8 may be oxidized with an oxidant such as sulfur t ⁇ oxide pyndine complex in DMSO and tnethylamme to provide the ketone 9 as a mixture of diastereomers.
- an oxidant such as sulfur t ⁇ oxide pyndine complex in DMSO and tnethylamme
- Treatment of ketone 9 with triethylamine in CD ⁇ OD D 2 0 at reflux provides the deuterated analog as a mixture of diastereomers which are separated by
- protective groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and denvatives thereof as known to the art Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
- Acid addition salts of the compound of Formula (I) are prepared in a standard manner m a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfunc, phosphoric, acetic, tnfluoroacetic, maleic, succmic or methanesulfonic acid
- an acid such as hydrochloric, hydrobromic, hydrofluoric, sulfunc, phosphoric, acetic, tnfluoroacetic, maleic, succmic or methanesulfonic acid
- novel Intermediate also provides a novel intermediate, 3-methylbenzofuran-2- carboxyhc acid ⁇ (S)-3 -methyl- 1 -[3-hydroxy- 1 -( 1 -oxy-py ⁇ dme-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ am ⁇ de (8-Scheme-l), of Formula (II), useful in the synthesis of the compound of Formula (I) according to Scheme 1
- the present invention provides a process for the synthesis of compounds of Formula (I) comprising the step of oxidizing the appropriate compound of Formula (II) with an oxidant to provide the compound of Formula (I) as a mixture of diastereomers.
- the oxidant is sulfur tnoxide pyndine complex m DMSO and tnethylamme.
- the present invention also provides a process for the synthesis of deuterated compounds of Formula (I) Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuteratmg the protonated isomer with a deuteratmg agent to provide the deuterated compound of Formula (I) as a mixture of diastereomers is added to the synthesis.
- the deuteratmg agent is CD 3 OD:D 2 0 (10: 1) in tnethylamme.
- the process further comprises the step of separating the diasteromers of Formula
- the present compound of Formula I exhibits superior chiral stability compared to the protonated isomer.
- This invention also provides a pharmaceutical composition which comprises a compound according to Formula (I) and a pharmaceutically acceptable earner, excipient or diluent Accordingly, the compound of Formula (I) may be used in the manufacture of a medicament
- Pharmaceutical compositions of the compound of Formula (I) prepared as hereinbefore described may be formulated as solutions or lyophihzed powders for parenteral administration Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable earner prior to use
- the liquid formulation may be a buffered, isotonic, aqueous solution
- suitable diluents are normal isotonic saline solution, standard 5% dextrose in water, or buffered sodium or ammonium acetate solution
- Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or ne
- the compound of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository
- the compound of Formula (I) is useful as a protease inhibitor, particularly as an inhibitor of cysteine and serme proteases, more particularly as an inhibitor of cysteine proteases, even more particularly as an inhibitor of cysteine proteases of the papain superfamily, yet more particularly as an inhibitor of cysteine proteases of the cathepsin family, most particularly as an inhibitor of cathepsin K
- the present invention also provides useful compositions and formulations of said compound, including pharmaceutical compositions and formulations of said compound
- the present compound is useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata, as well as in schistosomiasis, malana, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly
- Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the sunounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compound of this invention
- the present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise admmistenng to an animal, particularly a mammal, most particularly a human in need thereof the compound of the present invention
- the present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise admmistenng to an animal, particularly a mammal, most particularly a human m need thereof, an inhibitor of cathepsin K, including the compound of the present invention
- the present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis cannn, trypsanoma cruzi, trypsanoma brucei, and Cnthidia fusiculata, as well as in schi
- an effective amount of the compound of Formula (I) is administered to inhibit the protease implicated in a particular condition or disease
- this dosage amount will further be modified according to the type of administration of the compound
- parenteral administration of the compound of Formula (I) is preferred
- An intravenous infusion of the compound m 5% dextrose in water or normal salme, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful
- the parenteral dose will be about 0.01 to about 100 mg/kg, preferably between 0 1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K.
- the compound is administered one to four times daily at a level to achieve a total daily dose of about 0 4 to about 400 mg/kg day.
- the precise amount of the inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect
- Prodrugs of the compound of the present invention may be prepared by any suitable method Where the prodrug moiety is a ketone functionality, specifically ketals and/or hemiacetals, the conversion may be effected m accordance with conventional methods
- the compound of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein.
- a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient Preferably the oral dose would be about 0.5 to about 20 mg/kg No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention
- Standard assay conditions for the determination of kinetic constants used a fluorogemc peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5 5 containing 20 mM cysteine and 5 mM EDTA Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 ⁇ M final substrate concentration in the assays. All assays contained 10% DMSO Independent expenments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature. Product fluorescence (excitation at 360 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product
- [AMC] v ss t + (. o - ss) [1 - exp f-k o bs J k 0 bs (2)
- the compounds used in the method of the present invention have a K j value of less than 1 micromolar
- said compounds have a K j value of less than 100 nanomolar
- the cells were washed x2 with cold RPMI-1640 by centnfugation (1000 rpm, 5 mm at 4°C) and then transferred to a sterile 15 mL centrifuge tube The number of mononuclear cells were enumerated m an improved Neubauer counting chamber
- Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative) The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice The suspension was mixed frequently The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast- ⁇ ch fraction) were decanted into a stenle 50 mL centnmge tube Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts This wash process was repeated xlO The bead-coated cells were discarded
- the osteoclasts were enumerated m a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample
- the cells were pelleted by centnfugation and the density of osteoclasts adjusted to 1 5xl ⁇ 4/mL in EMEM medium, supplemented with 10% fetal calf serum and 1 7g/htre of sodium bicarbonate 3 mL ahquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes These cells were pelleted by centnfugation To each tube 3 mL of the appropriate treatment was added (diluted to 50 ⁇ M in the EMEM medium) Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL) The tubes were incubated at 37°C for 30 minutes
- the TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by somcation Pit volumes were determined using the Nikon/Lasertec ILM21 W confocal microscope
- reaction was filtered to remove the catalyst and the filtrate was concentrated to provide
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Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001536515A JP2003533432A (ja) | 1999-11-10 | 2000-11-08 | プロテア−ゼ阻害剤 |
EP00977056A EP1351930A4 (fr) | 1999-11-10 | 2000-11-08 | Inhibiteurs de la protease |
AU14747/01A AU1474701A (en) | 1999-11-10 | 2000-11-08 | Protease inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16456199P | 1999-11-10 | 1999-11-10 | |
US60/164,561 | 1999-11-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001034566A2 true WO2001034566A2 (fr) | 2001-05-17 |
WO2001034566A3 WO2001034566A3 (fr) | 2003-07-31 |
Family
ID=22595065
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/030682 WO2001034566A2 (fr) | 1999-11-10 | 2000-11-08 | Inhibiteurs de la protease |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1351930A4 (fr) |
JP (1) | JP2003533432A (fr) |
AU (1) | AU1474701A (fr) |
WO (1) | WO2001034566A2 (fr) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6534498B1 (en) | 1999-11-10 | 2003-03-18 | Smithkline Beecham Corporation | Protease inhibitors |
EP1303281A1 (fr) * | 2000-04-18 | 2003-04-23 | SmithKline Beecham Corporation | Methodes de traitement |
US6583137B1 (en) | 1999-11-10 | 2003-06-24 | Smithkline Beecham Corporation | Protease inhibitors |
US6596715B1 (en) | 1999-11-10 | 2003-07-22 | Smithkline Beecham Corporation | Protease inhibitors |
US7071184B2 (en) | 2000-03-21 | 2006-07-04 | Smithkline Beecham Corporation | Protease inhibitors |
US7405209B2 (en) | 1998-12-23 | 2008-07-29 | Smithkline Beecham Corporation | Protease inhibitors |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ511710A (en) * | 1998-12-23 | 2003-12-19 | Smithkline Beecham Corp | 4-Amino-azepan-3-one derivatives useful as protease inhibitors |
CN105288305A (zh) * | 2015-11-30 | 2016-02-03 | 延欣虹 | 一种治疗口腔上火及牙龈肿痛的药物组合物及其制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000038687A1 (fr) * | 1998-12-23 | 2000-07-06 | Smithkline Beecham Corporation | Inhibiteurs de proteases |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DZ2285A1 (fr) * | 1996-08-08 | 2002-12-25 | Smithkline Beecham Corp | Inhibiteurs de protéase de la cystéine. |
-
2000
- 2000-11-08 JP JP2001536515A patent/JP2003533432A/ja not_active Withdrawn
- 2000-11-08 EP EP00977056A patent/EP1351930A4/fr not_active Withdrawn
- 2000-11-08 AU AU14747/01A patent/AU1474701A/en not_active Abandoned
- 2000-11-08 WO PCT/US2000/030682 patent/WO2001034566A2/fr not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000038687A1 (fr) * | 1998-12-23 | 2000-07-06 | Smithkline Beecham Corporation | Inhibiteurs de proteases |
Non-Patent Citations (1)
Title |
---|
See also references of EP1351930A2 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7405209B2 (en) | 1998-12-23 | 2008-07-29 | Smithkline Beecham Corporation | Protease inhibitors |
US6534498B1 (en) | 1999-11-10 | 2003-03-18 | Smithkline Beecham Corporation | Protease inhibitors |
US6583137B1 (en) | 1999-11-10 | 2003-06-24 | Smithkline Beecham Corporation | Protease inhibitors |
US6596715B1 (en) | 1999-11-10 | 2003-07-22 | Smithkline Beecham Corporation | Protease inhibitors |
US7071184B2 (en) | 2000-03-21 | 2006-07-04 | Smithkline Beecham Corporation | Protease inhibitors |
US7563784B2 (en) | 2000-03-21 | 2009-07-21 | Smithkline Beecham Corporation | Protease inhibitors |
EP1303281A1 (fr) * | 2000-04-18 | 2003-04-23 | SmithKline Beecham Corporation | Methodes de traitement |
EP1303281A4 (fr) * | 2000-04-18 | 2006-02-15 | Smithkline Beecham Corp | Methodes de traitement |
Also Published As
Publication number | Publication date |
---|---|
WO2001034566A3 (fr) | 2003-07-31 |
AU1474701A (en) | 2001-06-06 |
JP2003533432A (ja) | 2003-11-11 |
EP1351930A2 (fr) | 2003-10-15 |
EP1351930A4 (fr) | 2004-09-15 |
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