WO1997005865A1 - C-proteinase inhibitors for the treatment of disorders related to the overproduction of collagen - Google Patents
C-proteinase inhibitors for the treatment of disorders related to the overproduction of collagen Download PDFInfo
- Publication number
- WO1997005865A1 WO1997005865A1 PCT/US1996/012876 US9612876W WO9705865A1 WO 1997005865 A1 WO1997005865 A1 WO 1997005865A1 US 9612876 W US9612876 W US 9612876W WO 9705865 A1 WO9705865 A1 WO 9705865A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- mono
- group
- sulfonyl
- compound
- Prior art date
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- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
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- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Definitions
- Collagen is integral to, among other things, the proper formation of connective tissue.
- the over- or under-production of collagen or the production of abnormal collagen has been linked with numerous connective tissue diseases and disorders.
- C-proteinase is an essential key enzyme for the proper maturation of collagen, and therefore appears to be an ideal target for the inhibition, control and/or modulation of collagen formation.
- Collagen Structure At present nineteen types of collagens have been identified. These collagens, including fibrillar collagen types I, II, III are synthesized as procollagen precursor molecules which contain amino- and carboxy-terminal peptide extensions. These peptide extensions, referred to as “pro-regions, " are designated as N- and C-propeptides, respectively.
- a partially purified protein having C-proteinase activity was obtained from chick calvaria in 1982. Njieha et al. , 1982, Biochemistry 23:757-764.
- chicken C-proteinase was isolated, purified and characterized from 0 conditioned media of chick embryo tendons. Hojima et al. , 1985, J. Biol. Chem. 260: 15996-16003.
- Murine C-proteinase has been subsequently purified from media of cultured mouse fibroblasts. Kessler et al. , 1986, Collagen Relat. Res. 6:249-266; Kessler and Adar, 1989, Eur. J. Biochem. 186:115- 121.
- the cDNA encoding human C-proteinase has been identified, as 5 set forth in the above-referenced related applications and references disclosed therein.
- the present invention relates to organic molecules capable of modulating, regulating and/or inhibiting production and/or maturation of collagen by affecting C-proteinase activity.
- the compounds of the present invention have the formulae:
- R 4 is selected from the group consisting of H, lower alkyl
- R 5 is selected from the group consisting of H, lower alkyl, carboxyalkyl, (mono- or dialkylamino)alkyl, alkyl-(thio, sufinyl or sulfonyl)alkyl, alkoyalkylacylalkyl;
- R is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl;
- R 3 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl; j is selected from the group consisting of H, lower alkyl; R 5 is selected from the group consisting of H, lower alkyl, carboxyalkyl, (mono- or dialkylamino)alkyl, alkyl-(thio, sufmyl or sul
- R 2 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl;
- R 3 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl;
- fibrotic disorders may be induced or initiated by surgery such as scar revision/plastic surgeries, glaucoma, cataract fibrosis, corneal scarring, joint adhesions, graft vs. host disease, tendon surgery, nerve entrapment, dupuytren's contracture, OB/GYN adhesions/fibrosis, pelvic adhesions, peridural fibrosis, restenosis. Still further fibrotic disorders may be induced l" by chemotherapy, including, for example lung fibrosis and the like.
- Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral 25 delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intra ventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
- Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
- Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
- the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g. , dichlorodifluoromethane, trichlorofluoromethane,
- Capsules and cartridges of, e.g. , gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
- compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles
- Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
- the suspension may also contain suitable stabilizers or agents which increase the
- the implantation for example subcutaneously or intramuscularly
- intramuscular injection for example, the
- 35 compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
- the cosolvent system may be the VPD co-solvent system.
- VPD is a solution of 3 % w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80,
- co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g.
- organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
- the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
- sustained-release materials have been established and are well known by those
- Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
- compositions suitable for use in the 2 " present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the 25 capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
- the therapeutically effective dose can be estimated imtially from cell culmre assays.
- a dose can be formulated in animal models to achieve a • - * -'" circulating concentration range that includes the IC 50 as determined in cell culmre (i. e. , the concentration of the test compound which achieves a half-
- a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient.
- Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell culmres or experimental animals, e.g. , for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
- Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culmre assays and animal studies can be used in formulating a range of dosage for use in human.
- Dosage intervals can also be determined using MEC value.
- Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% .
- the effective local concentration of the drug may not be related to plasma concentration.
- compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
- the pack may, for example, comprise metal or plastic foil, such as a blister pack.
- the pack or dispenser device may be * accompanied by instructions for administration.
- Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of arthritis or any other fibrotic disorder.
- Boc-Glu (OBn)OH and Boc-Asp(OBn)OH have been synthesized using methods readily known in the art.
- reaction mixmre was allowed to warm to -30°C over 2h, then a 40% aquoeus solution of methyl amine (22 mmol) was add, and the reaction mixmre was allowed to warm to room temperamre. After the reaction had stirred for a further hour, diethyl ether (50 ml) and water (70 ml) were added. The organic layer was separated, washed with 1 M NaHCO 3 , 10% citric acid, and saturated NaCI solution, and dried over MgSO 4 . The solvent was evaporated in vacuo to give a white solid (5.0 g, 72% yield).
- ester hydroxamate (28) also designated as FG-058, as a white solid.
- Methoxybenzenesulfonyl)-L-proline hydroxamate also designated as FG054, (Example for Inhibitor A) is as follows:
- N-Benzyloxy-N'-(4-Methoxybenzenesulfonyl)- ⁇ -benzyl-(L)-aspartic amide (41).
- N-(4-methoxybenzenesulfonyl)-b-benzyl- (L)-aspartic acid 300 mg, 0.76 mmol
- O- benzylhydroxylamine/HCl in an 0 anhydride solution of (7/3) THF/DMF (10 ml) was added
- the following assay may be used to determine the level of activity and effect of the different compounds of the present invention on C-proteinase activity.
- radiolabeled ( 14 C) procollagen is added to 10 units/ml of chicken C-proteinase in a solution of 0.1 M Tris-HCI, 0.1 M NaCI, 0.02%
- the protein bands are detected by autoradiography.
- the amount of enzyme activity is based on the disappearance of the band conesponding to uncleaved procollagen.
- the IC 50 of inhibitors can be determined by plotting the % activity versus inhibitor concentration and estimating the inhibitor concentration which results in 50% activity.
- TABLE I IC S0 Of Various Identified C-Proteinase Inhibitors.
- the IC 50 value of the inhibitors can also be determined by a filtration ELISA assay.
- a filtration ELISA assay In this assay about 25 ng of unlabeled human procollagen I were incubated with the C-Proteinase as, see, section 6.2.1 but for one hour. The reaction was stopped with the addition of 40 ⁇ l precipitation buffer (0.5 X Reaction buffer, 0.1 mg/ml chicken collagen II, 10 ⁇ g/ml BSA, 7.5 mM EDTA). 25 ⁇ l of 75% ethanol was added and the reactions were mixed and incubated on ice for one hour to precipitate the procollagen.
- 40 ⁇ l precipitation buffer 0.5 X Reaction buffer, 0.1 mg/ml chicken collagen II, 10 ⁇ g/ml BSA, 7.5 mM EDTA
- the soluble c-propeptide was separated from the precipitated collagen by filtering through a Millipore multiscreen-HV 0.45 ⁇ m hydrophilic plate using a Millipore multiscreen vacuum manifold. 20 ⁇ l of the filtrate was removed and the amount of cleaved c-propeptide was determined by using the procollagen type I C-peptide (PIP) EIA kit from Takara Biomedicals.
- PIP procollagen type I C-peptide
- IC 50 of the inhibitors was determined by plotting the % activity * * ⁇ " versus inhibitor concentration and estimating the inhibitor concentration which gives 50 % activity. IC 50 values are shown in TABLE II
- tissue culture assays by measurement of the production of procollagen and mature collagen in conditioned medium before and after treatment with a compound.
- the ratio of collagen and procollagen will directly conelate to the cellular conversion of the precursor to the mature collagen product, and as such indicate the C-proteinase activity.
- the media content of C-propeptide/cell may be determined, and compared for untreated cells and inhibitor-treated cells.
- animal models which mimic clinical disorders related to unregulated or inappropriate collagen production are known in the art and may be employed to determine the in vivo efficacy of the compounds of the invention. These animal models include a wound chamber model in rats (Schilling et al., 1959, Surgery 46:702-710), an estradiol stimulated uterus expansion model (Mandell et al., 1982, The Journal of Biological Chemistry 257:5268-5273), and an induced angiogenesis model (Matrigel) (Passaniti et al, 1992, Laboratory Investigation 67:519-528).
- liver fibrosis models include clinical disorder models like liver fibrosis models (Tsukamoto et al., 1990, Seminar in Liver Disease 10:56-65; Kock-Weser, 1952, Laboratory Investigation 1:324-331 ; Manione, 1949, American Journal of Pathology 25:273-285; Tarns, 1957, American Journal of Pathology 33:13-27; Wahl et ai, 1986, Journal of Experimental Medicine 163:884-902), a pulmonary fibrosis model (Kelly et ai, 1980, Journal of Laboratory Clinical Medicine 96:954-964), arterial restenosis models (Jackson, 1994, Trends of Cardiovascular Medicine 4:122-130; Clowes et al., 1983, Laboratory Investigation 49:327-333), a kidney fibrosis model (Yamamoto et al, 1987, Kidney International 3_2:514-525), a tendon repairing model (Franklin et al,
- Cytotoxicity is evaluated as a function of cellular survival and cell proliferation.
- Cellular survival involves the use of quiescent cells and is determined by cell number (counting or staining). A decrease in cell number indicates cell loss, and thus an effect on cell survival.
- Cell proliferation involves the use of rapidly proliferating cells and is, as well, determined by cell number. Here a decrease in cell number relative to the untreated controls indicates an effect on cell proliferation.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR9609883A BR9609883A (pt) | 1995-08-08 | 1996-08-08 | Composto tendo efeito inibidor em proteinase c composição farmacéutica e processo para tratar doenças relacionadas com a produção inapropriada ou desregulada de colágeno |
AU69512/96A AU6951296A (en) | 1995-08-08 | 1996-08-08 | C-proteinase inhibitors for the treatment of disorders related to the overproduction of collagen |
MX9801093A MX9801093A (es) | 1995-08-08 | 1996-08-08 | Inhibidores de la proteinasa c para el tratamiento de enfermedades relacionadas con la sobreproduccion de colagena. |
EP96930499A EP0845987A4 (en) | 1995-08-08 | 1996-08-08 | C-PROTEINASE INHIBITORS FOR THE TREATMENT OF CONDITIONS RELATED TO COLLAGEN OVERPRODUCTION |
JP9508648A JPH11511137A (ja) | 1995-08-08 | 1996-08-08 | コラーゲンの過剰生産に関係した疾患を治療するためのc−プロテイナーゼ阻害剤 |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US203895P | 1995-08-08 | 1995-08-08 | |
US60120396A | 1996-02-14 | 1996-02-14 | |
US60918796A | 1996-03-01 | 1996-03-01 | |
US609,187 | 1996-03-01 | ||
US601,203 | 1996-03-01 | ||
US60/002,038 | 1996-03-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997005865A1 true WO1997005865A1 (en) | 1997-02-20 |
Family
ID=27357060
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/012876 WO1997005865A1 (en) | 1995-08-08 | 1996-08-08 | C-proteinase inhibitors for the treatment of disorders related to the overproduction of collagen |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0845987A4 (ko) |
JP (1) | JPH11511137A (ko) |
KR (1) | KR19990036271A (ko) |
CN (1) | CN1198096A (ko) |
AU (1) | AU6951296A (ko) |
BR (1) | BR9609883A (ko) |
CA (1) | CA2229098A1 (ko) |
MX (1) | MX9801093A (ko) |
WO (1) | WO1997005865A1 (ko) |
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US6462063B1 (en) | 2000-02-04 | 2002-10-08 | Fibrogen, Inc. | C-proteinase inhibitors |
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US6645993B2 (en) | 2001-03-30 | 2003-11-11 | Warner-Lambert Company | 3-heterocyclylpropanohydroxamic acid PCP inhibitors |
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US5863949A (en) * | 1995-03-08 | 1999-01-26 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
EP0871710A1 (en) * | 1995-08-08 | 1998-10-21 | Thomas Jefferson University | Recombinant c-proteinase and processes, methods and uses thereof |
EP0871710A4 (en) * | 1995-08-08 | 2001-03-07 | Univ Jefferson | RECOMBINANT PROTEINASE C AND PROCESSES, METHODS AND USES |
US6747027B1 (en) | 1996-07-22 | 2004-06-08 | Pharmacia Corporation | Thiol sulfonamide metalloprotease inhibitors |
US6013649A (en) * | 1996-07-22 | 2000-01-11 | Monsanto Company | Thiol sulfone metalloprotease inhibitors |
US6153609A (en) * | 1996-08-23 | 2000-11-28 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
US5998412A (en) * | 1997-01-23 | 1999-12-07 | Syntex (U.S.A.) Inc. | Sulfamide-metalloprotease inhibitors |
US6143744A (en) * | 1997-01-23 | 2000-11-07 | Syntex (U.S.A.) Inc. | Sulfamide-metalloprotease inhibitors |
US6376506B1 (en) | 1997-01-23 | 2002-04-23 | Syntex (U.S.A.) Llc | Sulfamide-metalloprotease inhibitors |
WO1998042659A3 (en) * | 1997-03-26 | 1999-02-25 | Smithkline Beecham Plc | Aryl- or heteroarylsulfonamide substituted hydroxamic acid derivates, process for their preparation and their use as pharmaceuticals |
WO1998042659A2 (en) * | 1997-03-26 | 1998-10-01 | Smithkline Beecham Plc | Aryl- or heteroarylsulfonamide substituted hydroxamic acid derivates, process for their preparation and their use as pharmaceuticals |
US6242467B1 (en) | 1997-03-26 | 2001-06-05 | Smithkline Beecham P.L.C. | Compounds |
US6037139A (en) * | 1997-06-03 | 2000-03-14 | Wisconsin Alumni Research Foundation | System for assaying modulators of procollagen maturation |
WO1998055862A1 (en) * | 1997-06-03 | 1998-12-10 | Wisconsin Alumni Research Foundation | System for assaying modulators of procollagen maturation |
US6423729B1 (en) | 1997-07-22 | 2002-07-23 | Shionogi & Co., Ltd. | Therapeutic or prophylactic agent for glomerulopathy |
US6878739B2 (en) | 1997-07-22 | 2005-04-12 | Shionogi & Co., Ltd. | Composition for treating or preventing glomerulopathy |
WO1999006340A3 (en) * | 1997-07-31 | 1999-09-30 | Procter & Gamble | Sulfonylamino substituted hydroxamic acid derivatives as metalloprotease inhibitors |
WO1999006340A2 (en) * | 1997-07-31 | 1999-02-11 | The Procter & Gamble Company | Sulfonylamino substituted hydroxamic acid derivatives as metalloprotease inhibitors |
US6218389B1 (en) | 1997-07-31 | 2001-04-17 | The Procter & Gamble Co. | Acyclic metalloprotease inhibitors |
US6130220A (en) * | 1997-10-16 | 2000-10-10 | Syntex (Usa) Inc. | Sulfamide-metalloprotease inhibitors |
WO1999032451A1 (en) * | 1997-12-19 | 1999-07-01 | Amgen Inc. | Azepine or larger medium ring derivatives and their use as pharmaceuticals |
US6107291A (en) * | 1997-12-19 | 2000-08-22 | Amgen Inc. | Azepine or larger medium ring derivatives and methods of use |
US6147074A (en) * | 1998-07-27 | 2000-11-14 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
US5994351A (en) * | 1998-07-27 | 1999-11-30 | Pfizer Inc. | Arylsulfonylamino hydroxamic acid derivatives |
US6107337A (en) * | 1998-08-06 | 2000-08-22 | Pfizer Inc. | Arylsulfonylamino hydroxamic acid derivatives |
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Also Published As
Publication number | Publication date |
---|---|
BR9609883A (pt) | 1999-03-23 |
CA2229098A1 (en) | 1997-02-20 |
AU6951296A (en) | 1997-03-05 |
EP0845987A4 (en) | 2000-05-24 |
CN1198096A (zh) | 1998-11-04 |
EP0845987A1 (en) | 1998-06-10 |
MX9801093A (es) | 1998-04-30 |
KR19990036271A (ko) | 1999-05-25 |
JPH11511137A (ja) | 1999-09-28 |
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