WO2008131481A1 - Traitement de maladies mésangioprolifératives - Google Patents

Traitement de maladies mésangioprolifératives Download PDF

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Publication number
WO2008131481A1
WO2008131481A1 PCT/AU2008/000576 AU2008000576W WO2008131481A1 WO 2008131481 A1 WO2008131481 A1 WO 2008131481A1 AU 2008000576 W AU2008000576 W AU 2008000576W WO 2008131481 A1 WO2008131481 A1 WO 2008131481A1
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Prior art keywords
tranilast
group
formula
type compound
compound
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PCT/AU2008/000576
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English (en)
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Darren James Kelly
Richard Ernest Gilbert
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Fibrotech Therapeutics Pty Ltd
The University Of Melbourne
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Priority claimed from AU2007902202A external-priority patent/AU2007902202A0/en
Application filed by Fibrotech Therapeutics Pty Ltd, The University Of Melbourne filed Critical Fibrotech Therapeutics Pty Ltd
Publication of WO2008131481A1 publication Critical patent/WO2008131481A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the invention relates to methods and compositions for treatment of a mesangioproliferative disease, including IgA deposition diseases, in particular IgA nephropathy.
  • Mesangial proliferative glomerulonephritis is a kidney disorder characterised clinically by nephrotic syndrome (protein loss in the urine and swelling of the body). It may be present as acute, chronic, or rapidly progressive glomerulonephritis, and may progress to chronic renal failure. It is seen more commonly in lupus patients who develop glomerulonephritis, and in patients who have Immunoglobulin A (IgA) nephropathy.
  • IgA Immunoglobulin A
  • IgA nephropathy is the commonest primary glomerulonephritis in the world. While initially viewed as a relatively benign disease, recent studies have highlighted the poor prognosis in some with end-stage renal disease developing in 15- 40% of patients [Donadio and Grande, N Engl J Med. 2002 Sep 5; 347(10):738-48 2002] despite the widespread use of ACE inhibitors. Histopathologically, IgA nephropathy is characterised by increased mesangial cell number and glomerular matrix accumulation implicating growth factors with proproliferative and pro-fibrotic activity as pathogenetic factors.
  • IgA Immunoglobulin A
  • DH Dermatitis herpetiformis
  • HS Henoch-Schonlein purpura
  • the present invention relates to methods for treating a mesangioproliferative disease, in particular IgA nephropathy, in a subject suffering from the disease.
  • the methods include administering to the subject a therapeutically effective amount of at least one tranilast- type compound, or a pharmaceutically acceptable salt or solvate thereof.
  • Treating a mesangioproliferative disease includes inhibiting the progression of the mesangioproliferative disease, preventing the mesangioproliferative disease, and/or ameliorating a symptom of the mesangioproliferative disease.
  • the invention relates to a method for treating a mesangioproliferative disease, in a subject comprising administering to the subject a therapeutically effective amount of a tranilast-type compound, or a pharmaceutically acceptable salt or solvate thereof, or a medicament comprising a tranilast-type compound and a pharmaceutically acceptable carrier, excipient, or vehicle, which results in beneficial effects following treatment.
  • the invention relates to a method of treatment comprising administering a therapeutically effective amount of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof, which upon administration to a subject with symptoms of a mesangioproliferative disease, produces beneficial effects, in particular sustained beneficial effects.
  • the mesangioproliferative disease may be an IgA deposition disease.
  • the mesangioproliferative disease is IgA nephropathy.
  • the method of treatment includes administering a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof, which upon administration to a subject with symptoms of a mesangioproliferative disease produces a beneficial effect, in particular a sustained beneficial effect.
  • the beneficial effect is evidenced by one or more of: reduction or inhibition of PDGF activity, reduction or inhibition of TGF- ⁇ activity, reduction or inhibition of PDGF-induced mesangial cell proliferation, reduction or inhibition of mesangial cell numbers, reduction or inhibition of glomerular matrix accumulation, reduction or elimination of IgA deposition in the glomerular mesangium, reduction or elimination of macroscopic hematuria, reduction or elimination of proteinuria, and reduction or elimination of hypertension.
  • the invention provides a method involving administering to a subject a therapeutically effective amount of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof, which inhibits or reduces IgA deposition or which causes dissolution and/or disruption of pre-existing IgA aggregates.
  • the present invention provides a method of preventing or reducing proteinuria in a subject including administering to the subject a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of reversing or reducing IgA deposition in glomerular mesangium after the onset of symptoms of IgA nephropathy in a subject including administering to the subject a therapeutically effective amount for reversing or reducing IgA deposition in glomerular mesangium after the onset of symptoms of IgA nephropathy, of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method for amelioriating a symptom of an IgA deposition disease, in particular IgA nephropathy, comprising administering a therapeutically effective amount for amelioriating a symptom of an IgA deposition disease, in particular IgA nephropathy, of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method for ameiioriating progression of an IgA deposition disease, in particular IgA nephropathy, comprising administering a therapeutically effective amount for ameiioriating progression of an IgA deposition disease, in particular IgA nephropathy, of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof.
  • the invention relates to a method of delaying the progression of an IgA deposition disease, in particular IgA nephropathy, comprising administering a therapeutically effective amount for delaying the progression of IgA nephropathy of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof.
  • the present invention relates to a method of increasing survival or improving the lifespan of a subject suffering from a mesangioproliferative disease, in particular IgA nephropathy, including administering a therapeutically effective amount for increasing survival or improving a lifespan of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof.
  • the tranilast-type compound may be administered as a pharmaceutical composition as described herein.
  • the present invention provides a pharmaceutical composition for treating a mesangioproliferative disease, in particular IgA nephropathy, including a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof.
  • the tranilast-type compound is a compound of formula I
  • R-i and R 2 which may be the same or different, are selected from the group consisting of a Ci to C-io alkyl, C 3 to Cio cycloalkyl, C 3 to Ci 0 cycloalkylmethyl, C 3 to do alkene, C 3 to C 10 alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;
  • Xi and X 2 are the same or different and are selected from the group consisting of a bond, O, N and S;
  • T is a single or double bond
  • R 3 is selected from the group consisting of H, C 3 to do alkene, C 3 to do alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;
  • R 4 is selected from the group consisting of H, OH, OR 6 , NHR 6 and NR 6 Rz;
  • R5 is selected from the group consisting of H, NHR 6 , NR 6 R 7 , ORs, halogen, C 3 to do alkene, C 3 to do alkyne and a chain consisting of a heterocyclic or fused ring, any of which may be optionally substituted;
  • R 6 and R 7 which may be the same or different, are selected from the group consisting of H, C 1 to Ci 0 alkyl, C 3 to do cycloalkyl, C 3 to C 10 cycloalkylmethyl, C 3 to C 10 alkene, C 3 to C 10 alkyne, aryl, C 5 to C 20 alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted;
  • Rs is selected from the group consisting of H, Ci to C 10 alkyl, C 3 to C 10 cycloalkyl, C 3 to Cio cycloalkylmethyl, C 3 to C-io alkene, C 3 to C 10 alkyne, aryl, C 5 to C 2 o alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; and
  • n is an integer between 0 and 4.
  • R 1 and R 2 are the same or different and are selected from the group consisting of optionally substituted Ci to Ci 0 alkyl, optionally substituted C 2 to do alkynyl and a chain including an optionally substituted triazole.
  • R 3 and R 4 are the same or different and are selected from the group consisting of OH, hydrogen, halogen, optionally substituted Ci to Cio alkyl and optionally substituted C 2 to Cio alkynyl.
  • one of Ri and R 2 is methyl and the other of Ri and R 2 is propargyl or a chain containing a 1 ,4- disubstituted 1 ,2,3-triazole.
  • the compound of formula I can not be tranilast (N-[3,4- dimethoxycinnamoyl]anthranilic acid).
  • the present invention provides a pharmaceutical composition in a form adapted for administration to a subject to provide beneficial effects in the treatment of a mesangioproliferative disease, in particular IgA nephropathy.
  • the present invention provides a pharmaceutical composition for treating a mesangioproliferative disease, in particular IgA nephropathy, including a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, excipient or vehicle.
  • the present invention provides a pharmaceutical composition including at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof in a therapeutically effective amount for reducing and/or eliminating proteinuria in a subject suffering from IgA nephropathy.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier, excipient, or vehicle.
  • the present invention provides the use of at least one tranilast- type compound or a pharmaceutically acceptable salt or solvate thereof for the preparation of a pharmaceutical composition for treating a mesangioproliferative disease, in particular IgA nephropathy.
  • the present invention additionally provides a method of preparing a stable pharmaceutical composition including at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof in a therapeutically effective amount for treating a mesangioproliferative disease, in particular IgA nephropathy.
  • the present invention provides a kit for treating a mesangioproliferative disease, in particular IgA nephropathy, including:
  • Glomerular cellularity as assessed by the number of nuclei per glomerular cross-section (GCS) in 50 hilar glomeruli per animal. Glomerular hypercellularity was increased in Thy-1 nephritis and attenuated by tranilast. Data are expressed as mean ⁇ SEM. *P ⁇ 0.05 versus control; tP ⁇ 0.05 versus Thy-1.
  • Data are expressed as (mean ⁇ SEM) per glomerular cross- section (gcs) in 50 hilar glomeruli per animal from untreated and tranilast-treated rats. *P ⁇ 0.05 versus control; tP ⁇ 0.01 versus Thy-1.
  • Glomerular cellularity as assessed by the number of nuclei per glomerular cross-section (gcs) in 50 hilar glomeruli per animal in H & E stained sections. Glomerular hypercellularity was significantly attenuated by FT011. Data are expressed as mean + SEM. *P ⁇ 0.05 versus controls; # P ⁇ 0.05 versus untreated.
  • Glomerular mesangial expansion was significantly increased in Anti-Thy-1 rats and attenuated by FT011. Data are expressed as mean ⁇ SEM. *P ⁇ 0.05 versus controls; # P ⁇ 0.05 versus untreated.
  • Activated mesangial cells Data are expressed as the proportional area of ⁇ -smooth muscle actin immunostaining (mean ⁇ SEM) per glomerular cross-section (gcs) in 50 hilar glomeruli per animal from untreated and FT011-treated rats. * P ⁇ 0.01 versus control; *P ⁇ 0.05 versus untreated.
  • Type IV collagen deposition Data are expressed as proportional area (mean ⁇ SEM) of collagen IV immunostaining per glomerular cross-section (gcs) in 50 hilar glomeruli per animal from untreated and FT011 -treated rats. *P ⁇ 0.01 versus control; # P ⁇ 0.05 versus untreated.
  • ED-1 ED-1 positive cells per glomerular cross-section
  • a "beneficial effect” refers to an effect of a tranilast-type compound or pharmaceutical composition thereof, including favorable pharmacological and/or therapeutic effects, and improved biological activity.
  • the beneficial effects may include one or more of the following: reduction or inhibition of PDGF activity, reduction or inhibition of TGF- ⁇ activity, reduction or inhibition of PDGF-induced mesangial cell proliferation, reduction or inhibition of mesangial cell numbers, reduction or inhibition of glomerular matrix accumulation, reduction or elimination of IgA deposition in the glomerular mesangium, reduction or elimination of macroscopic hematuria, reduction or elimination of proteinuria, and/or reduction or elimination of hypertension.
  • the beneficial effect is a "sustained beneficial effect" where the beneficial effect is sustained for a prolonged period of time after termination of treatment.
  • a treatment can be sustained over several years thereby having a major beneficial impact on the severity of the disease and its complications.
  • a beneficial effect may be sustained for a prolonged period of at least about 2 to 4 weeks, 2 to 5 weeks, 3 to 5 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 14 weeks, 2 to 16 weeks, 2 to 20 weeks, 2 to 24 weeks, 2 weeks to 12 months, 2 weeks to 18 months, 2 weeks to 24 months, or several years following treatment.
  • the period of time a beneficial effect is sustained may correlate with the duration and timing of the treatment.
  • a subject may be treated continuously for about or at least about 2 to 4 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 14 weeks, 2 to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, or several years, periodically or continuously.
  • the beneficial effect may be a statistically significant effect in terms of statistical analysis of an effect of a tranilast-type compound, versus the effects without such a compound.
  • "Statistically significant” or “significantly different” effects or levels may represent levels that are higher or lower than a standard. In embodiments of the invention, the difference may be 1.5, 2, 3, 4, 5, or 6 times higher or lower compared with the effect obtained without a tranilast-type compound.
  • pharmaceutically acceptable carrier, excipient, or vehicle refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered.
  • a carrier, excipient, or vehicle may include diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous material such as absorbents that may be needed in order to prepare a particular pharmaceutical composition.
  • carriers etc. include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art.
  • “Therapeutically effective amount” relates to the amount or dose of a tranilast-type compound or pharmaceutical composition thereof, that will lead to one or more desired effects, in particular, one or more beneficial effects.
  • a therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the substance to elicit a desired response in the subject.
  • a dosage regimen may be adjusted to provide the optimum therapeutic response (e.g. sustained beneficial effects). For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a therapeutically effective amount includes a prophyiactically effective amount.
  • Mesangioproliferative Disease “Mesangial proliferative glomerulonephritis (MPGN)” or “Mesangioproliferative glomerulonephritis” refer to any disease or condition involving proliferation of mesangial cells and are used interchangeably herein. Characteristic light microscopic findings of this disease are expansion of the mesangium with little or no involvement of the capillary lumina.
  • Mesangial cell proliferation may be accompanied by an increase in mesangial matrix and in advanced cases by mesangial sclerosis, lmmunohistochemistry studies may reveal deposits of IgA (IgA nephropathy) or, IgG, IgM, C3 and C1q in the glomerular capillary wall or mesangium.
  • IgA IgA nephropathy
  • IgG IgG
  • IgM IgM
  • C3 and C1q in the glomerular capillary wall or mesangium.
  • the presence of deposits is not an obligate finding to making the diagnosis of MPGN.
  • Mesangioproliferative glomerulonephritis can be divided into two main groups: primary and secondary.
  • Primary Mesangioproliferative glomerulonephritis includes IgA nephropathy, non-lgA mesangial proliferative glomerulonephritis, IgM mesangial proliferative glomerulonephritis, and Henoch-Schoenlein purpura (i.e., a skin and kidney disease characterized by deposition of IgAI in skin tissue and kidney).
  • the secondary forms accompany a wide range of diseases, such as systemic lupus erythematosus, glomerulonephritis with hepatitis and vasculitis, multiple sclerosis, and rheumatoid arthritis.
  • IgA deposition disease refers to any disease characterised by the deposition of immunoglobulin A (IgA) in tissue or organs. Such diseases include, but are not limited to, IgA neuropathy, dermatitis herpetiformis and Henoch-Schonlein purpura. In an IgA deposition disease, IgA may be deposited in immune complexes in tissue, such as the skin and kidney.
  • IgA immunoglobulin A
  • IgA nephropathy refers to a kidney disease characterized by IgAI deposits within the kidney.
  • tranilast-type compound includes tranilast (N-(3,4-dimethoxycinnamoyl)anthranilic acid) and derivatives thereof, may include those disclosed in US patent no 3,940,422.
  • tranilast-type compounds examples include a compound of the formula I
  • R 1 and R 2 which may be the same or different, are selected from the group consisting of a Ci to C 10 alkyl, C 3 to C 10 cycloalkyl, C 3 to do cycloalkylmethyl, C 3 to C 10 alkene, C 3 to do alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;
  • Xi and X 2 are the same or different and are selected from the group consisting of a bond, O, N and S;
  • T is a single or double bond
  • R 3 is selected from the group consisting of H, C 3 to do alkene, C 3 to C 10 alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;
  • R 4 is selected from the group consisting of H, OH, OR 6 , NHRe and NR 6 R 7 ;
  • R 5 is selected from the group consisting of H, NHR 6 , NR 6 R 7 , ORs, halogen, C 3 to do alkene, C 3 to C 10 alkyne and a chain consisting of a heterocyclic or fused ring, any of which may be optionally substituted;
  • Re and R 7 which may be the same or different, are selected from the group consisting of H, C 1 to C-io alkyl, C 3 to do cycloalkyl, C 3 to do cycloalkylmethyl, C 3 to C 10 alkene, C 3 to do alkyne, aryl, C 5 to C 20 alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted;
  • Rs is selected from the group consisting of H, Ci to Ct 0 alkyl, C 3 to C 10 cycloalkyl, C 3 to C1 0 cycloalkylmethyl, C 3 to C- 10 alkene, C 3 to Ci 0 alkyne, aryl, C 5 to C2 0 alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; and
  • n is an integer between 0 and 4.
  • Ri or R 2 when Xi and X 2 are both O or a bond, and one of Ri or R 2 is a Ci to C 4 alkyl, the other of Ri or R 2 is a C 4 to C 10 alkyl, C 3 to C 10 cycloalkyl, C 3 to C 10 cycloalkylmethyl, C 3 to C 1O alkyne, or a chain containing a heterocyclic fused ring.
  • the compound of Formula excludes tranilast (3,4- dimethoxycinnamoyl)anthranilic acid.
  • the tranilast-type compound is a compound of the Formula Il
  • Rg or R 40 which may be the same or different, are selected from the group consisting of H, C-i to C 10 alkyl, C 3 to Cs terminal or non-terminal alkyne or a cyclopentyl, cyclohexyl, cyclohexylmethyl or cyclopentylmethyl group.
  • Ri or R 2 of Formula Il when one of Ri or R 2 of Formula Il is a Ci to C 4 alkyl, the other of R 1 or R 2 is a C4 to C 10 alkyl, C 3 to C 1 O cycloalkyl, C 3 to C 10 cycloalkylmethyl, C 3 to C 10 alkyne or a chain containing a heterocyclic or fused ring, any of which are optionally substituted.
  • the compound of Formula Il excludes tranilast (3,4- dimethoxycinnamoyl)anthranilic acid.
  • the tranilast-type compound is a compound of the Formula III or Formula IV
  • G is a cyclopentyl ring, a cyclohexyl ring or a 1 ,4-disubstituted 1 ,2,3-triazole ring;
  • q is an integer between O and 6.
  • the tranilast-type compound is a compound of the formula V
  • R 5 is optionally substituted methyl, ethyl, propyl, hydroxyl or halogen; and R 6 is an optionally substituted alkynyl, in particular a C 2 to C 1 O alkynyl or a chain containing an optionally substituted triazole.
  • Re is propargyl or a 1 ,4-disubstituted 1 ,2,3-triazole.
  • R 5 is methyl and R 6 is propargyl.
  • the compound of Formula V excludes tranilast (3,4- dimethoxycinnamoyl)anthranilic acid .
  • the tranilast-type compound has the formula Vl
  • n is an integer between 1 and 10, preferably 1 and 6; and R is hydrogen or Ci to do alkyl.
  • the tranilast-type compound has the formula VII
  • n is an integer between 1 and 10, preferably 1 and 6; and R is hydrogen or optionally substituted Ci to C-io alkyl.
  • the tranilast-type compound has the formula VIII
  • n is an integer between 1 and 10, preferably 1 and 6; and R is hydrogen or any one of the following optionally substituted groups, alkyl, in particular Ci to Ci 0 alkyl, aryl, arylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, alkylamido, aminoalkyl, acylamino and arylamido.
  • the tranilast-type compound has the formula IX
  • n is an integer between 1 and 10, preferably 1 and 6; and R is hydrogen, or any one of the following optionally substituted groups, alkyl, in particular Ci to Ci 0 alkyl, aryl, arylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, alkylamido, aminoalkyl, acylamino and arylamido.
  • the tranilast-type compound is selected from Group A, consisting of
  • the tranilast-type compound is selected from Group B, consisting of
  • the tranilast-type compound a the compound of the formula X
  • the compound of the formula X is also referred to as FT011.
  • a tranilast-type compound also includes a prodrug of the compounds described above.
  • prodrug refers to a tranilast-type compound including structural modifications thereto, such that in vivo the prodrug is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage into a parent compound (e.g., active compound or active derivative or analogue thereof).
  • the term includes bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. Examples of barriers include, without limitation, solubility, permeability, stability, presystemic metabolism and targeting limitations (J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004).
  • Prodrugs may be, for example, metabolically labile mono- or di-ester derivatives of a parent compound having a carboxylic acid group.
  • a tranilast-type compound also includes a derivative or analogue of the compounds described above.
  • “Derivatives” include functional derivatives, chemical derivatives, or variants.
  • a “functional derivative” refers to a compound that possesses an activity (either functional or structural) that is substantially similar to the activity of a described tranilast-type compound.
  • the term “chemical derivative” describes a molecule that contains additional chemical moieties which are not normally a part of the base molecule.
  • variant is meant to refer to a molecule substantially similar in structure and/or biological activity to a compound or parts thereof.
  • the term “analogue” includes a compound substantially similar in function to a compound described above.
  • An “analogue” can include a chemical compound that is structurally similar to another but differs slightly in composition. Differences include without limitation the replacement of an atom or functional group with an atom or functional group of a different element.
  • a tranilast-type compound encompasses all possible enantiomers, stereoisomers including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures and tautomers of the compounds described above.
  • a tranilast-type compound also includes an isotopically labelled compound described above, for example, a compound incorporating at least one 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, or 17 O, atom.
  • Suitable salts include salts that may be formed where acidic protons in the compounds are capable of reacting with inorganic or organic bases.
  • Suitable inorganic salts include those formed with alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminium.
  • Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • Suitable salts include acid addition salts formed with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g.
  • a pharmaceutically acceptable salt may be a mono-acid-mono-salt or a di-salt; and similarly where there are more than two acidic groups present, some or all of such groups can be salified.
  • Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, as
  • alkyl either alone or within other terms such as “arylalkyl”, means a monovalent, saturated hydrocarbon radical which may be a straight chain (i.e. linear) or a branched chain.
  • an alkyl radical includes from about 1 to 24 or 1 to 20 carbon atoms, preferably from about 1 to 10, 1 to 8, 3 to 8, 1 to 6, or 1 to 3 carbon atoms.
  • alkyl radicals include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, sec-butyl, tert-butyl, tert- pentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, n-dodecyl, n-tetradecyl, pentadecyl, n-hexadecyl, heptadecyl, n-octadecyl, nonadecyl, eicosyl, dosyl, n-tetracosyl, and the like, along with branched variations thereof.
  • an alkyl radical is a CrC ⁇ lower alkyl including or selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, isopropyl, isobutyl, isopentyl, amyl, tributyl, sec-butyl, tert-butyl, tert-pentyl, and n- hexyl.
  • the alkyl radical may be substituted with substituents at positions that do not significantly interfere with the preparation of tranilast-type compounds and that do not significantly reduce the efficacy of the compounds.
  • the alkyl radicals may be substituted with one to five substituents including halo, lower alkoxy, hydroxyl, cyano, nitro, thio, alkenyl, alkynyl, amino, substituted amino, carboxyl, sulfonyl, sulfenyl, sulfinyl, sulfate, sulfoxide, substituted carboxyl, halogenated lower alkyl (e.g.
  • CF 3 halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, aryl (e.g., phenylmethyl), heteroaryl (e.g., pyridyl), heterocyclyl (e.g., piperidinyl, morpholinyl) and by groups as described below.
  • aryl e.g., phenylmethyl
  • heteroaryl e.g., pyridyl
  • heterocyclyl e.g., piperidinyl, morpholinyl
  • alkenyl refers to an unsaturated, acyclic branched or straight-chain hydrocarbon radical including at least one double bond.
  • Alkenyl radicals may contain from about 2 to 24 or 2 to 10 carbon atoms, preferably from about 3 to 8 carbon atoms and more preferably about 3 to 6 or 2 to 6 carbon atoms.
  • alkenyl radicals examples include ethenyl, propenyl such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1 -yl (allyl), prop-2-en-2-yl, buten-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but ⁇ 2-en-2-yl, buta-1,3-dien-1-yl, buta-1 ,3-dien-2-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
  • the alkenyl radical may be substituted with those substituents listed above in relation to the term alkyl or by groups as described below.
  • alkynyl refers to an unsaturated, branched or straight-chain hydrocarbon radical including one or more triple bonds.
  • Alkynyl radicals may contain about 1 to 20, 1 to 15, or 2 to 10 carbon atoms, preferably about 3 to 8 carbon atoms and more preferably about 3 to 6 carbon atoms.
  • alkynyl radicals examples include ethynyl, such as prop-1-yn-1-yl, prop-2-yn-1 -yl (propargyl), butynyls such as but-1-yn-1- yl, but-1-yn-3-yl, but-3-yn-1-yl, pentynyls such as pentyn-1-yl, pentyn-2-yl, 4- methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexynyls such as hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, and 3,3-dimethylbutyn-1-yl radicals and the like.
  • ethynyl such as prop-1-yn-1-yl, prop-2-yn-1 -yl (propargyl)
  • butynyls such as but-1-yn-1- yl, but-1
  • alkynyl radical is defined as being optionally substituted
  • the alkynyl radical may be substituted with those substituents listed above in relation to the term alkyl or by groups as described below.
  • cycloalkynyl refers to cyclic alkynyl groups.
  • alkoxy refers to a linear or branched oxy-containing radical having an alkyl portion of one to about ten carbon atoms, such as a methoxy radical.
  • Particular alkoxy radicals are "lower alkoxy” radicals having about 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • An alkoxy having about 1-6 carbon atoms includes a CrC ⁇ alkyl-O- radical wherein Cr C ⁇ alkyl has the meaning set out herein.
  • Illustrative examples of alkoxy radicals include without limitation methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy.
  • an "alkoxy" radical may be further substituted with one or more substituents including alkyl atoms (in particular lower alkyl) to provide “alkylalkoxy” radicals; halo, such as fluoro, chloro or bromo, to provide "haloalkoxy” radicals (e.g. fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy) and "haloalkoxyalkyl” radicals (e.g. fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl).
  • substituents including alkyl atoms (in particular lower alkyl) to provide “alkylalkoxy” radicals; halo, such as fluoro,
  • acyl alone or in combination, means a carbonyl or thiocarbonyl group bonded to a radical selected from, for example, optionally substituted, hydrido, alkyl (e.g. haloalkyl), alkenyl, alkynyl, alkoxy ("acyloxy” including acetyloxy, butyryloxy, iso- valeryloxy, phenylacetyloxy, benzoyloxy, p-methoxybenzoyloxy, and substituted acyloxy such as alkoxyalkyl and haloalkoxy), aryl, halo, heterocyclyl, heteroaryl, sulfinyl (e.g.
  • alkylsulfinylalkyl sulfonyl (e.g. alkylsulfonylalkyl), cycloalkyl, cycloalkenyl, thioalkyl, thioaryl, amino (e.g alkylamino or dialkylamino), and aralkoxy.
  • acyl radicals are formyl, acetyl, 2-chloroacetyl, 2-bromacetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
  • cycloalkyl refers to radicals having from about 3 to 16 or 3 to 15 carbon atoms and containing one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantyl, and the like.
  • the cycloalkyl radicals are "lower cycloalkyl” radicals having from about 3 to 10, 3 to 8, 3 to 6, or 3 to 4 carbon atoms, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the term "cycloalkyl” also embraces radicals where cycloalkyl radicals are fused with aryl radicals or heterocyclyl radicals. Where a cycloalkyl radical is defined as being optionally substituted, the cycloalkyl radical may be substituted with groups as described below.
  • cycloalkenyl refers to a radical including about 2 to 16, 4 to 16, 2 to 15, 2 to 10, 4 to 10, 3 to 8, 3 to 6, or 4 to 6 carbon atoms, one or more carbon-carbon double bonds, and one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused.
  • the cycloalkenyl radicals are "lower cycloalkenyl” radicals having three to seven carbon atoms, in particular cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • cycloalkenyl radical is defined as being optionally substituted
  • the cycloalkyl radical may be substituted with groups as described below.
  • aryl alone or in combination, refers to a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused.
  • fused means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common or shared with the first ring.
  • an aryl radical has 4 to 24 carbon atoms, in particular 4 to 10, 4 to 8, or 4 to 6 carbon atoms.
  • aryl includes without limitation aromatic radicals such as phenyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indanyl, biphenyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl, preferably phenyl.
  • An aryl radical may be optionally substituted with groups as disclosed herein, in particular hydroxyl, alkyl, carbonyl, carboxyl, thiol, amino, and/or halo.
  • aralkyl used herein refers to an alkyl group with an aryl substituent
  • aralkenyl used herein refers to an alkenyl group with an aryl substituent
  • aralkynyl used herein refers to an alkynyl group with an aryl substituent.
  • substituted aryl radicals include benzyl, chlorobenyzl, and amino benzyl.
  • heteroatom refers to an atom other than carbon, e.g., a nitrogen, oxygen, sulfur or phosphorus atom.
  • a heteroatom-containing radical refers to a molecule or molecular fragment in which one or more carbon atoms is replaced with a heteroatom.
  • heteroalkyl refers to an alkyl substituent that is heteroatom- containing
  • heterocyclic refers to a cyclic substituent that is heteroatom- containing (see below)
  • heteroaryl refers to an aryl substituent that is heteroatom-containing (see below), and the like.
  • heteroaryl refers to fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 3 to 15, 3 to 10, 5 to 15, 5 to 10, or 5 to 8 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
  • a heteroaryl radical may contain one, two or three rings and the rings may be attached in a pendant manner or may be fused.
  • heteroaryl radicals include without limitation, an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and the like; an unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, in particular, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl and the like; an unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, in particular, 2-furyl
  • heterocyclic radicals are fused with aryl radicals, in particular bicyclic radicals such as benzofuran, benzothiophene, and the like.
  • aryl radicals such as benzofuran, benzothiophene, and the like.
  • a heteroaryl radical may be optionally substituted with groups as described below.
  • heterocyclic refers to saturated and partially saturated heteroatom- containing ring-shaped radicals having from about 3 to 15, 3 to 10, 5 to 15, 5 to 10, or 3 to 8 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
  • a heterocylic radical may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused.
  • saturated heterocyclic radicals include without limitation a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g.
  • partially saturated heterocyclyl radicals include without limitation dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • heterocyclic radicals include without limitation 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1 ,3-dioxolanyI, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, and the like.
  • a heterocyclic radical may be optionally substituted with groups as described below.
  • halo or halogen refers to fluoro, chloro, bromo and iodo, especially fluoro or chloro.
  • haloalkyl or haloalkenyl or haloalkynyl refer to an alkyl, alkenyl, or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.
  • amino refers to a radical where a nitrogen atom (N) is bonded to three substituents being any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or silyl with the general chemical formula -NR 10 Rn where Ri 0 and Rn can be any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, heteroaryl, or heterocyclic which may or may not be substituted.
  • one substituent on the nitrogen atom may be a hydroxyl group (- OH) to provide an amine known as a hydroxylamine.
  • amino groups are amino (-NH 2 ), alkylamino, acylamino, cycloamino, acycloalkylamino, arylamino, arylalkylamino, and lower alkylsilylamino, in particular methylamino, ethylamino, dimethylamino, 2-propylamino, butylamino, isobutylamino, cyclopropylamino, benzylamino, aliylamino, hydroxylamino, cyclohexylamino, piperidine, benzylamino, diphenylmethylamino, tritylamino, trimethylsilylamino, and dimethyl-tert- butylsilylamino.
  • “Amido” refers to a functional group containing a carbon atom double-bonded to an oxygen atom and additionally singly bonded to a nitrogen atom [-C(O)-N].
  • the term includes a primary amide i.e., an unsubstituted amide group [-C(O)-NH 2 ]; a secondary amide and a tertiary amide, i.e., amides in which nitrogen is substituted with one and two non-hydrogen groups respectively.
  • substituents apparent to a person skilled in the art may be used, including without limitation alkyl, alkenyl, alkynyl, alkanoyl, alkylene, alkenylene, hydroxyalkyl, haloalkyl, haloalkylene, haloalkenyl, alkoxy, alkenyloxy, alkenyloxyalkyl, alkoxyalkyl, aryl, alkylaryl, haloalkoxy, haloalkenyloxy, heterocyclic, heteroaryl, sulfonyl, sulfenyl, alkylsulfonyl, sulfinyl, alkylsulfinyl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, amino, oxy, halo
  • a tranilast-type compound may be prepared using reactions and methods generally known to the person of ordinary skill in the art, having regard to that knowledge and the disclosure of this application.
  • tranilast-type compounds have been synthesized and tested within the context of the treatment of allergies, as described in US 3,940,422.
  • Reactions for producing tranilast-type compounds are generally performed in a solvent appropriate to the reagents and materials used and suitable for the reactions being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the compounds should be consistent with the proposed reaction steps. This will sometimes require modification of the order of the synthetic steps or selection of one particular process scheme over another in order to obtain a desired tranilast-type compound.
  • tranilast-type compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or Lancaster Synthesis Inc. (Windham, N. H.) or are prepared by methods well known to a person of ordinary skill in the art, following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991 ; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols.
  • the starting materials, intermediates, and tranilast-type compounds may be isolated and purified using conventional techniques, such as precipitation, filtration, distillation, crystallization, chromatography, and the like. Tranilast-type compounds may be characterized using conventional methods, including physical constants and spectroscopic methods, in particular HPLC.
  • Tranilast-type compounds which are basic in nature can form a wide variety of different salts with various inorganic and organic acids.
  • In practice is it desirable to first isolate a tranilast-type compound from the reaction mixture as a pharmaceutically unacceptable salt and then convert the latter to the free base compound by treatment with an alkaline reagent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of base tranilast-type compounds are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • Tranilast-type compounds which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • These salts may be prepared by conventional techniques by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are typically employed to ensure completeness of reaction and maximum product yields.
  • the invention provides a pharmaceutical composition including a therapeutically effective amount of a tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof, for treating a mesangioproliferative disease, in particular IgA nephropathy, for treating symptoms caused by a mesangioproliferative disease, in particular IgA nephropathy, and/or for suppressing the progression thereof.
  • a pharmaceutical composition is in a form suitable for oral, topical, rectal, nasal, or parenteral administration.
  • the pharmaceutical composition may be in the form of a liquid solution, syrup, elixir, aqueous or oily suspension, emulsion, tablet, pill, capsule, lozenge, troche, powder, granule, emulsion, sustained release formulation, or powder.
  • compositions of the present invention or fractions thereof for pharmaceutical or veterinary use may include suitable pharmaceutically acceptable carriers, excipients, and vehicles selected based on the intended form of administration, and consistent with conventional pharmaceutical practices. Suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy (21 st Edition. University of the Sciences in Philadelphia (Editor), Mack Publishing Company).
  • the active components can be combined with oral, non-toxic pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital, and the like.
  • oral, non-toxic pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital, and the like.
  • the tranilast-type compounds may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Suitable binders e.g. gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes
  • lubricants e.g.
  • compositions as described herein can further include wetting or emulsifying agents, or pH buffering agents.
  • compositions for parenteral administration may include sterile aqueous or non-aqueous solvents, syrups, emulsions with edible oil, or other solvents conveniently used for parenteral administration of therapeutically active agents.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • aqueous solvents include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline, isotonic glucose solution, and buffered media.
  • a pharmaceutical composition intended for parenteral administration may also include conventional additives such as dispersing or suspending agents, stabilizers, buffers, or preservatives, e.g. antioxidants such as methylhydroxybenzoate or similar additives.
  • Dispersing or suspending agents that can be used for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, and polyvinylpyrrolidone.
  • a pharmaceutical composition including a tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof may also be in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art.
  • veterinary compositions include those adapted for:
  • oral administration for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
  • drenches e.g. aqueous or non-aqueous solutions or suspensions
  • tablets or boluses e.g. aqueous or non-aqueous solutions or suspensions
  • powders, granules or pellets for admixture with feed stuffs e.g. aqueous or non-aqueous solutions or suspensions
  • powders, granules or pellets for admixture with feed stuffs
  • pastes for application to the tongue for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
  • parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat;
  • topical applications e.g. as a cream, ointment or spray applied to the skin; or
  • intravaginally e.g. as a pessary, cream or foam.
  • a pharmaceutical composition of the invention may be sterilized by, for example, filtration through a bacteria retaining filter, addition of sterilizing agents to the pharmaceutical composition, irradiation of the pharmaceutical composition, or heating the pharmaceutical composition.
  • the compounds or compositions of the present invention may be provided as sterile solid preparations e.g. lyophilized powder, which are readily dissolved in sterile solvent immediately prior to use.
  • compositions After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition.
  • labeling would include amount, frequency, and method of administration.
  • kits include a tranilast- type compound or a pharmaceutical composition according to the present invention in kit form.
  • the kit can be a package which houses a container which contains a pharmaceutical composition according to the present invention and also houses instructions for administering the pharmaceutical composition to a subject.
  • a pharmaceutical pack or kit including one or more containers filled with one or more of the ingredients of a pharmaceutical composition according to the present invention to provide a beneficial effect, in particular a sustained beneficial effect.
  • Associated with such containers can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the labeling, manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • the invention contemplates the use of a tranilast-type compound or pharmaceutical composition including a tranilast-type compound for treating a mesangioproliferative disease, in particular preventing, and/or ameliorating disease severity, disease symptoms, and/or periodicity of recurrence of IgA nephropathy.
  • the invention contemplates treating in a mammal a mesangioproliferative disease, in particular IgA nephropathy using the pharmaceutical composition or treatments of the invention.
  • the mammal is a human.
  • a compound of the formula I to X or any one of Group A or Group B, preferably formula I is utilized in the treatment of a mesangioproliferative disease, in particular IgA nephropathy.
  • a mesangioproliferative disease in particular IgA nephropathy
  • Such treatment may be effective for retarding the effects of a mesangioproliferative disease, in particular IgA nephropathy, including specifically, but not exclusively, mesangial proliferation, matrix accumulation, macrophage infiltration, and proteinuria.
  • beneficial effects of a pharmaceutical composition or treatment of the invention for a mesangioproliferative disease, in particular IgA nephropathy can manifest as one or more or all of the following:
  • a) A reduction, slowing or prevention of an increase in, or an absence of symptoms of a mesangioproliferative disease, in particular IgA nephropathy, including without limitation proteinuria, hematuria, fatigue, malaise, myalgia, and/or hypertension, after administration to a subject with symptoms of IgA nephropathy.
  • a mesangioproliferative disease in particular IgA nephropathy, including without limitation proteinuria, hematuria, fatigue, malaise, myalgia, and/or hypertension
  • the compound induces at least about a
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in PDGF-induced mesangial cell proliferation.
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in mesangial cell numbers.
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in glomerular matrix accumulation.
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%,
  • TGF- ⁇ activity A reduction or inhibition of TGF- ⁇ activity relative to the amount measured in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy.
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction or inhibition of TGF- ⁇ activity.
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%,
  • hematuria in particular macroscopic hematuria relative to the amount in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy.
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction of hematuria, in particular macroscopic hematuria.
  • k A reduction or elimination of proteinuria relative to the amount in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy.
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction of proteinuria.
  • the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction of hypertension.
  • beneficial effects of a pharmaceutical composition or treatment of the invention can manifest as (a) and (b); (a), (b) and (c); (a), (b), (c) and (d); (a), (b), (C), (d), (e) and (f); (a), (b), (c), (d), (e), (f) and (g); (a) to (h); (a) to (i); (a) to G), (a) to (k), (a) to (I), (a) to (m), (a) to (n), or (a) to (o).
  • compositions and methods of the invention can be selected that have sustained beneficial effects, preferably statistically significant sustained beneficial effects.
  • a pharmaceutical composition with statistically significant sustained beneficial effects is provided including a therapeutically effective amount of a compound of the invention.
  • Greater efficacy and potency of a treatment of the invention in some aspects may improve the therapeutic ratio of treatment, reducing untoward side effects and toxicity.
  • Selected methods of the invention may also improve long-standing disease even when treatment is begun long after the appearance of symptoms.
  • Prolonged efficacious treatment can be achieved in accordance with the invention following administration of a tranilast-type compound, in particular a compound of the formula I to X or any one of Group A or Group B, preferably formula I, or pharmaceutical composition including same.
  • the invention provides a method for reducing proteinuria in a subject including administering to the subject a tranilast-type compound.
  • the invention provides a method for treating IgA nephropathy in a patient in need thereof which includes administering to the individual a pharmaceutical composition that provides a tranilast-type compound of the invention in a dose sufficient to reduce proteinuria in the patient.
  • the invention provides a method for treating IgA nephropathy including administering, preferably orally or systemically, an amount of a tranilast-type compound of the invention to a mammal, to reduce proteinuria, in particular for a prolonged period following administration.
  • the invention in an embodiment provides a method for treating a mesangioproliferative disease, in particular IgA nephropathy, the method including administering to a mammal in need thereof a pharmaceutical composition including a tranilast-type compound of the invention in an amount sufficient to reduce mesangial proliferation, matrix expansion and/or macrophage infiltration, preferably for a prolonged period following administration, thereby treating the mesangioproliferative disease, in particular IgA nephropathy.
  • the invention provides a method for treating an IgA nephropathy by providing a pharmaceutical composition including a tranilast-type compound of the invention in an amount sufficient to disrupt IgA deposition in a subject, in particular for a prolonged period following administration.
  • the method additionally includes determining the amount of IgA deposits.
  • the amount of IgA deposits may be measured using an antibody specific for IgA labeled with a detectable substance.
  • the invention provides a method for preventing and/or treating IgA nephropathy, the method including administering to a mammal in need thereof a pharmaceutical composition including a tranilast-type compound of the invention in an amount sufficient to disrupt IgA deposits, reduce mesangial proliferation, matrix expansion, proteinuria and/or macrophage infiltration preferably for a prolonged period following administration thereby treating the IgA nephropathy.
  • the present invention also includes methods and compositions of the invention in combination with one or more additional agents.
  • methods and pharmaceutical compositions for treating mesangioproliferative disease may include without limitation, ACE inhibitors, angiotensin Il receptor blockers, immuno-suppressive drugs such as azathioprine, prednisone, cyclophosphamide (e.g., Cytoxan), fish oil (omega-3 fatty acids), and mycophenolate mofetil, agents that are used for the treatment of complications resulting from or associated with a mesangioproliferative disease, or general medications that treat or prevent side effects.
  • immuno-suppressive drugs such as azathioprine, prednisone, cyclophosphamide (e.g., Cytoxan), fish oil (omega-3 fatty acids), and mycophenolate mofetil
  • agents that are used for the treatment of complications resulting from or associated with a mesangioproliferative disease or general medications that treat or prevent side effects
  • tranilast-type compound and the other agent(s) may be administered separately, sequentially or simultaneously.
  • the invention contemplates the use of at least one tranilast-type compound for the preparation of a pharmaceutical composition for treating a mesangioproliferative disease, in particular IgA nephropathy.
  • the invention additionally provides uses of a tranilast-type compound in the preparation of pharmaceutical compositions for the prevention and/or treatment of a mesangioproliferative disease, in particular IgA nephropathy.
  • the invention relates to the use of a therapeutically effective amount of at least one compound of the formula I to X or at least one compound of Group A and/or Group B for preparation of a pharmaceutical composition for providing therapeutic effects, in particular beneficial effects, preferably sustained beneficial effects, in treating a mesangioproliferative disease, in particular an IgA nephropathy.
  • the invention provides the use of a tranilast- type compound for the preparation of a pharmaceutical composition for prolonged or sustained treatment of a mesangioproliferative disease, in particular IgA nephropathy.
  • Therapeutic efficacy and toxicity of pharmaceutical compositions and methods of the invention may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals such as by calculating a statistical parameter such as the ED 50 (the dose that is therapeutically effective in 50% of the population) or LD 5O (the dose lethal to 50% of the population) statistics.
  • the therapeutic index is the dose ratio of therapeutic to toxic effects and it can be expressed as the ED 5 o/LD 5O ratio.
  • Pharmaceutical compositions which exhibit large therapeutic indices are preferred.
  • one or more of the therapeutic effects, in particular beneficial effects disclosed herein can be demonstrated in a subject or disease model, for example, Wister Kyoto rats with induced anti-Thy-1 nephritis as illustrated in the Example.
  • Compounds and pharmaceutical compositions of the present invention can be administered by any means that produce contact of the active agent(s) with the agent's sites of action in the body of a subject or patient to produce a therapeutic effect, in particular a beneficial effect, in particular a sustained beneficial effect.
  • the active ingredients can be administered simultaneously or sequentially and in any order at different points in time to provide the desired beneficial effects.
  • the tranilast-type compound or pharmaceutical composition according to the invention can be formulated for sustained release, for delivery locally or systemically. It lies within the capability of a skilled physician or veterinarian to select a form and route of administration that optimizes the effects of the pharmaceutical compositions and treatments of the present invention to provide therapeutic effects, in particular beneficial effects, more particularly sustained beneficial effects.
  • a tranilast-type compound or pharmaceutical composition may be suitable for oral, topical (including buccal and sublingual), ocular (including tear film, anterior chamber, posterior chamber or subretinal administration), rectal, nasal, vaginal or parenteral administration.
  • parenteral includes subcutaneous injections, aerosol for administration to lungs or nasal cavity, intravenous, intramuscular, intrathecal, intracranial, injection or infusion techniques.
  • a tranilast-type compound or pharmaceutical composition may be administered in an oral dosage form such as a tablet, capsule (each of which includes sustained release or timed release formulations), pill, powder, granule, elixir, tincture, suspension, syrup, and emulsion.
  • an oral dosage form such as a tablet, capsule (each of which includes sustained release or timed release formulations), pill, powder, granule, elixir, tincture, suspension, syrup, and emulsion.
  • a tranilast-type compound or pharmaceutical composition may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular forms, all utilizing dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • compositions of the invention may be administered by intranasal route via topical use of suitable intranasal vehicles, or via a transdermal route, for example using conventional transdermal skin patches.
  • a dosage protocol for administration using a transdermal delivery system may be continuous rather than intermittent throughout the dosage regimen.
  • a compound of Formula I to X or any one of Group A or Group B for in vivo application can be administered parenterally by injection or by gradual perfusion over time. Administration may be intravenously, intra-arterially, intraperitoneally, intramuscularly, subcutaneously, intracavity, transdermally or infusion by, for example, osmotic pump.
  • the dosage regimen of the invention will vary depending upon known factors such as the pharmacodynamic characteristics of the tranilast-type compound or pharmaceutical composition and their mode and route of administration; the species, age, sex, health, medical condition, and weight of the patient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, the route of administration, the renal and hepatic function of the patient, and the desired effect.
  • An amount of a therapeutic of the invention which will be effective in the treatment of a mesangioproliferative disease, in particular an IgA nephropathy, to provide therapeutic effects, in particular beneficial effects, more particularly sustained beneficial effects, can be determined by standard clinical techniques.
  • the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • Suitable dosage ranges for administration are particularly selected to provide therapeutic effects, in particular beneficial effects, more particularly sustained beneficial effects.
  • a dosage range is generally effective for triggering the desired biological responses.
  • the pharmacokinetics of orally administered tranilast have been studied in humans (Charng, etal., (2002) Journal of Food and Drug Analysis 10:135-138), and this information can be utilized by the skilled addressee in determining the dosage regimen of a traniiast-type compound.
  • a pharmaceutical composition or treatment of the invention may include a unit dosage of at least one tranilast-type compound.
  • a "unit dosage” or “dosage unit” refers to a unitary i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose including either the active agents as such or a mixture with one or more solid or liquid pharmaceutical excipients, carriers, or vehicles.
  • Dosage ranges for tranilast-type compounds are generally about 0.1 mg to about 2 g per kilogram body weight (assuming a 70 kg subject) per day.
  • the dosage range may be about 1 mg to about 200 mg per kg per day about 1 mg to about 200 mg per kg per day, about 1 mg to about 100 mg per kg per day, about 5 to 100 mg per kg per day, about 1 mg to about 50 mg per kg per day, about 2 to about 50 mg per kg per day, about 2 mg to about 40 mg per kg, about 2 mg to 30 mg per kg per day, about 2 to 20 mg per kg per day, about 2 to about 25 mg per kg per day, about 2 to 20 mg per kg per day, about 3 to 25 mg per kg per day, about 3 to 20 mg per kg per day, or about 3 to 15 mg per kg per day.
  • a pharmaceutical composition may include about 1 mg to about 1000 mg, about 50 mg to about 1000 mg, about 50 mg to about 900 mg, about 75 mg to about 900 mg, about 100 mg to about 900 mg, about 200 mg to about 900 mg, about 300 mg to about 900 mg, or about 100 mg to about 500 mg, about 100 mg to about 400 mg, or about 100 mg to about 300 mg, of a tranilast-type compound.
  • a dosage level of a tranilast-type compound in particular a compound of the formula I to X or any one of Group A or Group B is of the order of about 4 mg to about 13 mg per kilogram body weight (assuming a 70 kg subject) per day.
  • the amount of the compound of Formula I to X or any one of Group A or Group B which may be combined with the carrier materials to produce a single dosage will vary, depending upon the host treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain about 300 mg to 900mg of the compound with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition.
  • Unit dosages will generally contain between from about 100 mg to 300 mg of the compound of I to X or any one of Group A or Group B.
  • the daily doses of a tranilast-type compound may be from about 0.01 mg/kg per day to 1000 mg/kg per day. Small doses (0.01-1 mg) may be administered initially, followed by increasing doses up to about 1000 mg/kg per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localised delivery route) may be employed to the extent patient tolerance permits.
  • a subject may be treated with a compound of the formula I to X or any one of Group A or Group B or pharmaceutical composition or formulation thereof on substantially any desired schedule. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
  • a daily dose may be administered in one, two, three or four doses per day.
  • a pharmaceutical composition of the invention may be administered one or more times per day, in particular 1 or 2 times per day, once per week, once a month or continuously.
  • a subject may be treated less frequently, such as every other day or once a week, or more frequently.
  • a compound, pharmaceutical composition or formulation of the invention may be administered to a subject for about or at least about 1 week, 2 weeks to 4 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, or 2 weeks to 24 months, periodically or continuously.
  • the dosage ranges of a tranilast-type compound may be administered once twice, three times or more daily, especially once or twice daily.
  • a tranilast-type compound of the formula I to X or any one of Group A or Group B is administered in a divided dose schedule, such that there are at least two administrations in total in the schedule. Administrations are given preferably at least every two hours for up to four hours or longer; for example the compound may be administered every hour or every half hour.
  • the divided-dose regimen includes a second administration of the compound after an interval from the first administration sufficiently long that the level of the compound in the blood has decreased to approximately 5-30% of the maximum plasma level reached after the first administration, so as to maintain an effective content of the compound in the blood.
  • one or more subsequent administrations may be given at a corresponding interval from each preceding administration, preferably when the plasma level has decreased to approximately 10-50% of the immediately-preceding maximum.
  • the required dose of a compound disclosed herein, administered twice daily is about 1 to 50 mg/kg/day, 1 to 40 mg/kg/day, 3 to 40 mg/kg/day, 3 to 30 mg/kg/day, 3 to 25 mg/kg/day, most preferably 3 to 20 mg/kg/day.
  • Dosages of a tranilast-type compound, and related dosage regimes, that are particularly suitable for use in treating mesangioproliferative diseases include:
  • a daily dose of approximately 300mg of a tranilast-type compound which may be administered in a dosage regime of 100mg of a tranilast-type compound three times daily;
  • a daily dose of 600 to 900mg of a tranilast-type compound which may be administered in a dosage regime of 300 to 450mg of a tranilast-type compound twice daily.
  • Monoclonal OX-7, anti-rat Thy-1.1 antibody was used for the induction of mesangial proliferative glomerulonephritis. Macrophages were detected using ED1 , anti-rat CD68 and myofibroblasts were identified by labeling with 1A4, anti-human ⁇ -smooth muscle actin (Sigma Immunochemicals , St. Louis, MO, USA). A polyclonal goat anti- bovine/anti-human type IV collagen antibody (Southern Biotechnology, Birmingham, AL, USA) was used to examine extracellular matrix.
  • tranilast was prepared in dimethyl sulfoxide as 1000-fold stock solutions (DMSO). This stock solution was then diluted in cell culture medium to the required final concentration of 0 to 100 ⁇ mol/L.
  • DMSO dimethyl sulfoxide
  • FCS heat-inactivated fetal calf serum
  • tranilast was treated with 0 to 100 ⁇ mol/L tranilast for 4 hours prior to the addition of recombinant PDGF-BB 50 ng/mL (Sigma, St Louis, MO). Cells were incubated for a further 20 hours and 3 H thymidine (1 ⁇ Ci/well, Amersham Bioscience, Little Chalfont, Buckinghamshire, UK) was added for the last 4 hours of culture. Cells were washed twice in ice cold phosphate buffered saline (PBS), incubated in ice cold 10% TCA for 30 minutes, followed by a final
  • Lascorbic acid was incubated in the starve medium for 4 hours.
  • Cells were pretreated with 0-100 ⁇ M tranilast for 4 hours prior to the addition of PDGF-BB (50 ng/mL) and
  • RNAilast on PDGF receptor (PDGFR) activation cells were plated into 6-weII culture dishes in DMEM/10%FBS at low density and allowed to adhere overnight. The subconfluent cells were then starved overnight in DMEM/0.5%FBS, prior to pre-treatment with 0 to 100 ⁇ mol/L tranilast or without tranilast for 4 hours, followed by stimulation with PDGF-BB (50ng/mL).
  • cells were immediately placed on ice, washed once with ice-cold PBS, and lysed in 100 ⁇ of lysis buffer of 50 mM Tris, pH 7.4, 150 mM NaCl, 1mM EDTA, 1 mM EGTA, 0.5% Triton X-100, 0.5% lgepal CA-630, 0.1% SDS 1 1 mM Na vanadate, 50 mM NaF, 25 mM ⁇ glycerophosphate, 1OmM Na pyrophosphate, 10 ⁇ g/mL aprotinin, 10 ⁇ g/mL leupeptin, and 1 mM AEBSF.
  • lysis buffer 50 mM Tris, pH 7.4, 150 mM NaCl, 1mM EDTA, 1 mM EGTA, 0.5% Triton X-100, 0.5% lgepal CA-630, 0.1% SDS 1 1 mM Na vanadate, 50 mM NaF, 25 mM ⁇
  • Lysates were passed through a 21 G needle five times to aid solubilisation. Lysates were placed on ice for 30 minutes before centrifuging at 13,000 rpm at 4°C to remove cell debris, and protein concentration determined using the Bio-Rad Protein Assay (Bio-Rad Laboratories, Hercules, CA). Lysates were subjected to western blot analysis. In brief, samples with equal concentrations of protein were separated on 10% SDS-polyacrylamide gels transferred onto PVDF membranes (Roche Pharmaceuticals, Australia).
  • Membranes were blocked with 5% nonfat milk in TBST (Tris buffered saline, 0.1% Tween 20) before overnight incubation at 4 0 C with 1 :1000 rabbit anti-phosphorylated PDGFR- ⁇ (p-PDGFR- ⁇ ; Cell Signaling, Beverly, MA) in 5% bovine serum albumin (BSA). After extensive washes in TBST, membranes were incubated with horseradish peroxidase-conjugated anti-rabbit IgG (DAKO, Denmark) for 1 hour at room temperature. Signal was detected with enhanced chemiluminescent reagent and exposure to Hyperfilm (Amersham, Little Chalfont, UK).
  • TBST Tris buffered saline, 0.1% Tween 20
  • BSA bovine serum albumin
  • tranilast 400 mg/kg per day; Pharm Chemical, Shanghai Lansheng Corporation, Shanghai, China
  • vehicle control until killed on day 6, the peak of mesangial proliferation in this model.
  • the administration of tranilast was commenced 24 hours after OX-7 administration as mesangiolysis is complete by this time.
  • Tissues were fixed in 10% neutral-buffered formalin and embedded in paraffin. Kidney sections (4 ⁇ m) were stained with periodic acid-Schiffs reagent (PAS). Nuclei were counted in 50 hilar glomeruli in each animal.
  • PAS periodic acid-Schiffs reagent
  • kidney sections were rehydrated and treated with 1% H 2 O 2 /methanol followed by incubation in Protein Blocking Agent (Lipshaw-lmmunon, Pittsburgh, PA, USA) for 20 minutes at room temperature. Sections were then incubated with type IV collagen antibody for 60 minutes at room temperature, washed in PBS, and incubated with biotinylated goat anti-rabbit immunoglobulin (Dako, Carpinteria, CA, USA) followed by incubation with avidin-biotin peroxidase complex (ABC; Vector, Burlingham, CA, USA). Peroxidase conjugates were subsequently localized using diaminobenzidine tetrahydrochloride (DAB) as a chromogen. Sections were then counterstained with Mayer's hematoxylin.
  • DABC diaminobenzidine tetrahydrochloride
  • Immunostaining for ⁇ -smooth muscle actin was performed in formalin fixed tissue sections using a microwave-based technique to prevent antibody cross-reactivity.
  • sections were microwave treated for 10 minutes in 0.01 mol/L sodium citrate buffer, pH 6.0, and then labeled with ⁇ -smooth muscle actin antibody using a three- layer peroxidase-antiperoxidase method and developed with 3,3- DAB (Sigma) to produce a brown color.
  • Sections incubated with protein blocking agent instead of primary antisera served as negative controls. Tissues were also incubated with irrelevant isotype control antibodies. Tissues treated in this manner showed no positive staining.
  • Sections stained with ED1 antibody were scored manually counting immunolabelled cells in fifty hilar glomeruli in cross section under high power (x400) with the observer masked to the study group.
  • the magnitude of immunostaining for ⁇ -smooth muscle actin or type IV collagen was quantitated using computer-assisted image analysis.
  • images from three nonoverlapping, randomly selected fields were examined by light microscopy (Olympus BX-50; Olympus Optical, Tokyo, Japan) and digitized using a high-resolution camera (Fujix HC-2000; Fujifilm, Tokyo, Japan). All images were obtained using a 20 objective lens.
  • Digitized images were then captured on a Power Macintosh G3 computer (Apple Computer Inc., Cupertino, CA, USA) equipped with an in-built graphic board and opened using analytical software (Analytical Imaging Software, Ontario, Canada).
  • the area of brown on an immunoperoxidase-stained section was selected for its colour range, and the proportional area of tissue with this range of colour was then quantitated on 50 hilar glomeruli per animal such that the magnitude of immunolabeling was expressed as the proportional area of the tissue section that stained brown.
  • PDGF-induced 3 H-thymidine incorporation and 3 H-proline incorporation in mesangial cells were each inhibited by treatment of cells with tranilast in a dose-dependent fashion (Fig. 1).
  • PDGF-induced phosphorylation of PDGFR-/? was also inhibited by tranilast without affecting total PDGFR-/? ( Figure 2).
  • Mesangial cells remained viable, as evidenced by trypan blue exclusion and the maintenance of normal mesangial cell appearance, including nuclear morphology.
  • tranilast attenuates both the extent of histological injury and the magnitude of proteinuria.
  • this experiment shows that, in addition to ameliorating structural injury in the in vivo context, tranilast also abrogates
  • Anti-rat Thy-1.1 antibody (Monoclonal OX-7 IgG, gift from Dr. Nikolic-Paterson) was used for the induction of mesangial proliferative glomerulonephritis [1], macrophages were detected using ED1 , mouse anti-rat CD68 antibody (Serotec, Oxford, UK) [2].
  • Mouse anti-human ⁇ -smooth muscle actin (clone 1A4) antibody (DAKO, Denmark) was used to identify myofibroblasts.
  • a polyclonal goat anti-human type IV collagen antibody (Southern Biotechnology, Birmingham, AL, USA) was also used to examine extracellular matrix.
  • Kidney sections (4 ⁇ m) were stained with Haematoxylin and eosin (H & E) and periodic acid-Schiff s reagent (PAS). Quantitation of glomerular nuclei and mesangial expansion were performed by examining 50 hilar glomeruli per animal with light microscope.
  • kidney sections were rehydrated and treated with 3% H 2 O 2 followed by incubation in Protein Blocking Agent (Lipshaw-lmmunon, Pittsburgh, PA, USA) for 20 minutes at room temperature. Sections were then incubated with type IV collagen antibody (diluted 1 in 40 with PBS) for 60 minutes at room temperature, washed in PBS, and incubated with biotinylated rabbit anti-goat immunoglobulin (Dako, Carpinteria, CA, USA) followed by incubation with avidin-biotin peroxidase complex (ABC; Vector, Burlingham, CA, USA). Peroxidase conjugates were subsequently localized using diaminobenzidine tetrahydrochloride (DAB) as a chromogen. Sections were then counterstained with Mayer's hematoxylin.
  • DABC diaminobenzidine tetrahydrochloride
  • lmmunostaining for ⁇ -smooth muscle actin was performed in formalin fixed tissue sections using a microwave-based pre-treatment technique, as previously described [5].
  • sections were microwave treated for 10 minutes in 0.01mol/L sodium citrate buffer, pH 6.0, and then labeled with ⁇ -smooth muscle actin antibody (diluted 1 in 50 with PBS) using a three-layer peroxidase-antiperoxidase method and developed with 3,3-DAB (Sigma) to produce a brown color.
  • Digitized images were then captured on a Power Macintosh G5 computer (Apple Computer Inc., Cupertino, CA, USA) equipped with an in-built graphic board and opened using analytical software (Analytical Imaging Software, Ontario, Canada).
  • the area of magenta on a PAS stained or brown on an immunoperoxidase-stained section was selected for its colour range, and the proportional area of tissue with this range of colour was then quantitated on 50 hilar glomeruli per animal such that the magnitude of mesangial expansion and immunolabeling were expressed as the proportional area of the tissue section that stained magenta and brown, respectively.
  • FT011 The administration of FT011 was well tolerated by experimental animals with no weight loss or change in blood pressure (Table 2).
  • Table 2 Animal characteristics in control and experimental mesangial proliferative glomerulonephritis (Anti-Thy-1).

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Abstract

L'invention porte sur des compositions et des procédés pharmaceutiques comprenant des composés de type tranilast pour le traitement et/ou la prévention de maladies mésangioprolifératives. Dans des aspects de l'invention, des composés de type tranilast ou des compositions pharmaceutiques comprenant des composés de type tranilast sont utilisés dans le traitement et/ou la prévention de la néphropathie d'IgA.
PCT/AU2008/000576 2007-04-26 2008-04-24 Traitement de maladies mésangioprolifératives WO2008131481A1 (fr)

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WO2010071865A1 (fr) 2008-12-19 2010-06-24 Nuon Therapeutics, Inc. Compositions pharmaceutiques et procédés de traitement de l'hyperuricémie et des troubles associés
WO2012068612A1 (fr) * 2010-11-24 2012-05-31 Fibrotech Therapeutics Pty Ltd Méthodes de traitement de maladies oculaires associées à une inflammation et à une prolifération vasculaire
JP2017109982A (ja) * 2015-12-11 2017-06-22 ロート製薬株式会社 アントラニルアミド誘導体およびそれを含有するｔｌｒ３が関与する疾患の治療剤
WO2024159261A1 (fr) * 2023-01-31 2024-08-08 Certa Therapeutics Pty Ltd Formes solides, sels et polymorphes de composés antifibrotiques

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010071865A1 (fr) 2008-12-19 2010-06-24 Nuon Therapeutics, Inc. Compositions pharmaceutiques et procédés de traitement de l'hyperuricémie et des troubles associés
WO2012068612A1 (fr) * 2010-11-24 2012-05-31 Fibrotech Therapeutics Pty Ltd Méthodes de traitement de maladies oculaires associées à une inflammation et à une prolifération vasculaire
US20130310386A1 (en) * 2010-11-24 2013-11-21 Fibrotech Therapeutics Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
JP2014502267A (ja) * 2010-11-24 2014-01-30 フィブロテック セラピューティクス プロプライエタリー リミテッド 炎症及び血管増殖に関連する眼疾患の治療法
AU2011334592B2 (en) * 2010-11-24 2014-10-23 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
AU2011334592C1 (en) * 2010-11-24 2015-04-02 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
US9839640B2 (en) 2010-11-24 2017-12-12 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
US10695353B2 (en) 2010-11-24 2020-06-30 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
US10786510B2 (en) 2010-11-24 2020-09-29 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
US11583535B2 (en) 2010-11-24 2023-02-21 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
JP2017109982A (ja) * 2015-12-11 2017-06-22 ロート製薬株式会社 アントラニルアミド誘導体およびそれを含有するｔｌｒ３が関与する疾患の治療剤
WO2024159261A1 (fr) * 2023-01-31 2024-08-08 Certa Therapeutics Pty Ltd Formes solides, sels et polymorphes de composés antifibrotiques

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