US20120136066A1 - Glomerulonephritis Treatment - Google Patents

Glomerulonephritis Treatment Download PDF

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US20120136066A1
US20120136066A1 US13/375,618 US201013375618A US2012136066A1 US 20120136066 A1 US20120136066 A1 US 20120136066A1 US 201013375618 A US201013375618 A US 201013375618A US 2012136066 A1 US2012136066 A1 US 2012136066A1
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compound
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alkyl
carbonyl
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Berit Johansen
Andrea Huwiler
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AVVEXIN
Coegin Pharma AS
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Avexxin AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
    • 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
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • 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
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • 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
    • C07C323/52—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 the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to the use of certain polyunsaturated long-chain ketones for the treatment of glomerulonephritis and in particular to ketones carrying electron withdrawing substituents alpha to the carbonyl functionality in such treatment.
  • Glomerulonephritis also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys. It may present with isolated hematuria and/or proteinuria or as a nephrotic syndrome, acute renal failure, or chronic renal failure. Glomerulonephritis is categorised into several different pathological patterns, which are broadly grouped into non-proliferative or proliferative types. Diagnosing the pattern of GN is important because the outcome and treatment differs in different types.
  • glomerulonephritis Primary causes of glomerulonephritis are those which are intrinsic to the kidney, whilst secondary causes are associated with certain infections (bacterial, viral or parasitic pathogens), drugs, systemic disorders (SLE, vasculitis) or cancers.
  • the glomerulus is a unique vascular network with three specialised types of cell: the endothelial cell, the mesangial cell and the visceral epithelial cell
  • Mesangial cells serve a number of functions in the renal glomerular capillary including structural support of the capillary tuft, modulation of the glomerular hemodynamics and a phagocytic function allowing removal of macromolecules and immune complexes.
  • the proliferation of MC is a prominent feature of glomerular disease including IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy.
  • MC proliferation inhibitors may therefore offer therapeutic opportunities for the treatment of proliferative glomerular disease.
  • Mesangial proliferative glomerulonephritis is a form of glomerulonephritis which involves inflammation at the kidney glomeruli.
  • the mesangial cells which are a part of the glomerular capillaries increase in size giving the glomeruli a lumpy appearance.
  • the disorder usually causes nephritic syndrome which represents protein loss in the urine. It may be present as acute, chronic or rapidly progressive glomerulonephritis and may progress to chronic renal failure.
  • MC proliferation is inhibited by a variety of pharmacological drugs, for example inhibitors against angiotensin converting enzyme (ACE), cyclin-dependent kinases (CDK), platelet derived growth factor and others.
  • ACE angiotensin converting enzyme
  • CDK cyclin-dependent kinases
  • the glomerulus also has potential to express several isoforms of nitric oxide synthase (NOS).
  • NOS nitric oxide synthase
  • Induction of inducible NOS occurs as part of a rapid initial response to immune injury in a glomerulonephritis. Whilst the role of NO generated by NOS in the glomerulus is still unclear, some studies have demonstrated that NO inhibition can alter the level of proteinuria and leukocyte infiltration and other manifestations of injury such as thrombosis, proliferation and matrix production.
  • ACE angiotensin converting enzyme
  • the present inventors have realised that the compounds claimed herein, some of which are new, others known, have potential in the treatment of proliferative conditions in general and glomerulonephthritis in particular.
  • the inventors have found that a certain class of compounds based upon long chain unsaturated fatty acid molecules are useful in the treatment of glomerulonephritis.
  • R is a C 10-24 unsaturated hydrocarbon group optionally interrupted by one or more heteroatoms or groups of heteroatoms selected from S, O, N, SO, SO 2 , said hydrocarbon group comprising at least 4 non-conjugated double bonds;
  • L is a linking group forming a bridge of 1 to 5 atoms between the R group and the carbonyl CO;
  • X is an electron withdrawing group) or a salt thereof
  • the invention provides a method of treating glomerulonephritis comprising administering to an animal, preferably a mammal, e.g. human, an effective amount of a compound of formula (I) or a salt thereof as hereinbefore described.
  • the invention provides use of a compound of formula (I) or a salt thereof as hereinbefore described for use in the manufacture of a medicament for treating glomerulonephritis.
  • This invention involves the use of compounds of formula (I) or a salt thereof in the treatment of glomerulonephritis and related conditions.
  • Glomerulonephritis is a renal disease characterized by inflammation of the glomeruli.
  • the group R preferably comprises 5 to 9 double bonds, preferably 5 or 8 double bonds, e.g. 5 to 7 double bonds such as 5 or 6 double bonds. These bonds should be non-conjugated. It is also preferred if the double bonds do not conjugate with the carbonyl functionality.
  • the double bonds present in the group R may be in the cis or trans configuration however, it is preferred if the majority of the double bonds present (i.e. at least 50%) are in the cis configuration. In further advantageous embodiments all the double bonds in the group R are in the cis configuration or all double bonds are in the cis configuration except the double bond nearest the carbonyl group which may be in the trans configuration.
  • the group R may have between 10 and 24 carbon atoms, preferably 12 to 20 carbon atoms, especially 17 to 19 carbon atoms.
  • R group can be interrupted by at least one heteroatom or group of heteroatoms, this is not preferred and the R group backbone preferably contains only carbon atoms.
  • the R group may carry up to three substituents, e.g. selected from halo, C 1-6 alkyl e.g. methyl, C 1-6 alkoxy. If present, the substituents are preferably non-polar, and small, e.g. a methyl group. It is preferred however, if the R group remains unsubstituted.
  • substituents e.g. selected from halo, C 1-6 alkyl e.g. methyl, C 1-6 alkoxy. If present, the substituents are preferably non-polar, and small, e.g. a methyl group. It is preferred however, if the R group remains unsubstituted.
  • the R group is preferably linear. It preferably derives from a natural source such as a long chain fatty acid or ester. In particular, the R group may derive from AA, EHA or DHA.
  • the linking group L provides a bridging group of 1 to 5 backbone atoms, preferably 2 to 4 backbone atoms between the R group and the carbonyl.
  • the atoms in the backbone of the linker may be carbon and/or be heteroatoms such as N, O, S, SO, SO 2 .
  • the atoms can form part of a ring and the backbone atoms of the linking group can be substituted with side chains, e.g. with groups such as C 1-6 alkyl, oxo, alkoxy, or halo.
  • Preferred components of the linking group are —CH 2 —, —CH(C 1-6 alkyl)-, —N(C 1-6 alkyl)-, —NH—, —S—, —O—, —CH ⁇ CH—, —CO—, —SO—, —SO 2 — which can be combined with each other in any (chemically meaningful) order to form the linking group.
  • the linker —SCH 2 CH 2 — is formed.
  • linking group L contains at least one heteroatom in the backbone. It is also preferred if the first backbone atom of the linking group attached to the R group is a heteroatom or group of heteroatoms.
  • the linking group L contains at least one —CH 2 — link in the backbone. Ideally the atoms of the linking group adjacent the carbonyl are —CH 2 —.
  • the group R or the group L (depending on the size of the L group) provides a heteroatom or group of heteroatoms positioned ⁇ , ⁇ , ⁇ , or ⁇ to the carbonyl, preferably ⁇ or ⁇ to the carbonyl.
  • the heteroatom is O, N or S or a sulphur derivative such as SO.
  • linking groups therefore are —NH 2 CH 2 , —NH(Me)CH 2 —, —SCH 2 —, —SOCH 2 —, —COCH 2 —
  • the linking group is a ring or to comprise a ring.
  • the linker might be thiophene, e.g. 2,4-thiophene which provides a two atom bridge to the carbonyl (via the shortest route).
  • the linker would also be possible for the linker to be a ring such as furan, tetrahydrofuran, piperidine, cyclohexane, benzene or pyridine.
  • the linker comprises a ring it is preferred if this is a 5 or 6 membered ring.
  • the ring comprises at least one heteroatom or group of heteroatoms. It is preferred if the ring is unsaturated or aromatic.
  • the R and COX groups bind directly to such a ring, it is preferred if the R group and COX group bind on different atoms and preferred if they bind on carbon atoms of the ring.
  • substitution pattern is preferably such that the R and carbonyl substituents are alpha, gamma to each other (i.e. 1,3 or 2, 4 or 3, 5-split).
  • Suitable ring linkers are shown below where the R group and carbonyl can bind to any two carbon atoms on these rings:
  • the linker comprises a ring and non ring portion, e.g. CH 2 -thiophene or NH 2 -thiophene and so on.
  • the R group binds directly to the ring and that the carbonyl group binds to the non ring portion, e.g. a —CH 2 — linkage.
  • the skilled man will be able to devise all kinds of different linkers suitable for use in the invention.
  • Highly preferred linking groups are —CH 2 —, —CH 2 —CH 2 —, —CH(Me), —CH(Me)CH 2 —, —CH(Me)-CH(Me)-, SCH 2 , NHCH 2 , N(Me)CH 2 , 2,4-thiophene and 2,5-thiophene.
  • the group X is an electron withdrawing group.
  • Suitable groups in this regard include O—C 1-6 alkyl, CN, OCO 2 —C 1-6 alkyl, phenyl, CHal 3 , CHal 2 H, CHalH 2 wherein Hal represents a halogen, e.g. fluorine, chlorine, bromine or iodine, preferably fluorine.
  • the electron withdrawing group is CHal 3 , especially CF 3 .
  • preferred compounds of formula (I) are those of formula (I′)
  • Y1 is selected from O, S, NH, N(C 1-6 -alkyl), SO or SO 2 and
  • Y2 is (CH 2 ) n or CH(C 1-6 alkyl);
  • Y1 and Y2 taken together form a 5 or 6 membered homo or heterocyclic, optionally unsaturated or aromatic ring;
  • Y1 forms a 5 or 6 membered homo or heterocyclic, optionally unsaturated or aromatic ring and Y2 is (CH 2 ) n ;
  • n 1 to 3, preferably 1.
  • Y1 and Y2 taken together form a 5 or 6 membered homo or heterocyclic, optionally unsaturated or aromatic ring;
  • Y1 forms a 5 or 6 membered homo or heterocyclic, optionally unsaturated or aromatic ring and Y2 is (CH 2 ) n ;
  • n 1 to 3, preferably 1.
  • an L′ represents a linking group forming a bridge of 1 to 5 atoms between the R group and the carbonyl CO wherein said L′ linking group comprises a ring structure.
  • n 1 to 3, e.g. 1 to 2.
  • the groups bind to the 2 and 4 positions of the ring (where atom 1 is the S atom).
  • the invention provides a pharmaceutical composition comprising any new compound as hereinbefore defined in combination with at least one pharmaceutically acceptable excipient.
  • the compounds of the invention can be administered in salt, solvate, prodrug or ester form, especially salt form. Preferably however, no such form is used.
  • a pharmaceutical acceptable salt may be readily prepared by using a desired acid.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • an aqueous solution of an acid such as hydrochloric acid may be added to an aqueous suspension of a compound of formula (I) and the resulting mixture evaporated to dryness (lyophilised) to obtain the acid addition salt as a solid.
  • a compound of formula (I) may be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid may be added in the same solvent or another suitable solvent.
  • the resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.
  • Suitable addition salts are formed from inorganic or organic acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, trifluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, alkyl or aryl sulphonates (e.g.
  • methanesulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate) and isethionate include trifluoroacetate and formate salts, for example the bis or tris trifluoroacetate salts and the mono or diformate salts, in particular the tris or bis trifluoroacetate salt and the monoformate salt.
  • the compound of the invention is a sulphonium salt.
  • a sulphur atom in the backbone of the molecule e.g. in the linker group, is functionalised to carry a C1-6-alkyl group. This can be achieved through reaction with an alkyl halide, e.g. methyl iodide. The halide ion forms the counterion of the salt.
  • the invention provides a sulphonium salt of a compound of formula (I).
  • the compound is of formula (VI)
  • R and X are as hereinbefore defined and Z is a counterion, e.g. halide; e.g. the compound
  • Compounds of formula (I) may be manufactured using known chemical synthetic routes. It is convenient to begin synthesis from the commercially available compounds arachidonic acid (AA), EPA (all-Z-eicosa-5,8,11,14,17-pentaenoic acid) or DHA (all-Z-docosa-4,7,10,13,16,19-hexaenoic acid). Conversion of the acid functionality of these compounds into, for example a —COCF 3 group can be achieved readily, e.g. by converting the carboxylic acid into its corresponding acid chloride and reacting the same with trifluoroacetic anhydride in the presence of pyridine.
  • AA arachidonic acid
  • EPA all-Z-eicosa-5,8,11,14,17-pentaenoic acid
  • DHA all-Z-docosa-4,7,10,13,16,19-hexaenoic acid
  • the starting acid is reduced to an alcohol and, if required, converted to the corresponding thiol.
  • the nucleophilic thiol may then be reacted with a group such as BrCH 2 COCF 3 thereby introducing the carbonyl and electron withdrawing species.
  • a group such as BrCH 2 COCF 3
  • Methylation of the nitrogen can be effected before this reaction by the formation of an N—BOC group and reduction, e.g. with lithium aluminium hydride. Reaction with TFPO and oxidation yields the linker NMe-CH 2 .
  • treating or treatment is meant at least one of:
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician. In general a skilled man can appreciate when “treatment” occurs.
  • treatment is also used herein to cover prophylactic treatment, i.e. treating subjects who are at risk of developing a disease in question.
  • the compounds of the invention can be used on any animal subject, in particular a mammal and more particularly to a human or an animal serving as a model for a disease (e.g., mouse, monkey, etc.).
  • a mammal in particular a mammal and more particularly to a human or an animal serving as a model for a disease (e.g., mouse, monkey, etc.).
  • a “therapeutically effective amount” means the amount of a compound that, when administered to an animal for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated and will be ultimately at the discretion of the attendant doctor.
  • a compound of formula I may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, for example, wherein the agent is in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • carrier refers to a diluent, excipient, and/or vehicle with which an active compound is administered.
  • the pharmaceutical compositions of the invention may contain combinations of more than one carrier. Such pharmaceutical carriers are well known in the art.
  • the pharmaceutical compositions may also comprise any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s) and so on.
  • the compositions can also contain other active components, e.g. other drugs for the treatment of glomerulonephritis.
  • compositions for use in accordance with the present invention may be in the form of oral, parenteral, transdermal, inhalation, sublingual, topical, implant, nasal, or enterally administered (or other mucosally administered) suspensions, capsules or tablets, which may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • the compositions of the invention could also be formulated as nanoparticle formulations.
  • the compounds of the invention can be administered for immediate-, delayed-, modified-, sustained-, pulsed-or controlled-release applications.
  • compositions of the invention may contain from 0.01 to 99% weight—per volume of the active material.
  • a therapeutically effective amount of the compound of the present invention can be determined by methods known in the art.
  • the therapeutically effective quantities will depend on the age and on the general physiological condition of the patient, the route of administration and the pharmaceutical formulation used.
  • the therapeutic doses will generally be between about 10 and 2000 mg/day and preferably between about 30 and 1500 mg/day. Other ranges may be used, including, for example, 50-500 mg/day, 50-300 mg/day, 100-200 mg/day.
  • Administration may be once a day, twice a day, or more often, and may be decreased during a maintenance phase of the disease or disorder, e.g. once every second or third day instead of every day or twice a day.
  • the dose and the administration frequency will depend on the clinical signs, which confirm maintenance of the remission phase, with the reduction or absence of at least one or more preferably more than one clinical signs of the acute phase known to the person skilled in the art.
  • the compounds of the invention may be used in the treatment of glomerulonephritis and related diseases.
  • the compounds of the invention may be used to treat mesangioproliferative glomerulonephritis, nephrotic syndrome, chronic or acute renal failure, proteinuria, hematuria, IgA nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, and glomeruloscerlosis,
  • the compounds of the invention may be used to treat glomerulonephritis in combination with other known pharmaceuticals for said purpose and this forms a further aspect of the invention.
  • Other useful pharmaceuticals include corticosteriods, immunosuppressive drugs, antihypertensive agents and diuretic medications.
  • FIG. 1 shows the effect of the inhibitors of the examples on cytokine-stimulated PGE 2 formation in mesangial cells.
  • Quiescent cells were stimulated with either DMEM ( ⁇ ), IL-1 ⁇ (1 nM), in the absence ( ⁇ ) or presence of the indicated concentrations of AKH-217 and AVX002.
  • FIG. 2 shows the effect of the inhibitors of the examples on cytokine-stimulated sPLA 2 protein (A) and mRNA (B) expression and promoter activity in mesangial cells.
  • Quiescent cells were stimulated with either DMEM ( ⁇ ), or IL-1 ⁇ (1 nM) in the absence ( ⁇ ) or presence of AKH-217 (etOH), vehicle control.
  • FIG. 3 shows the effect of the inhibitors of the examples on cytokine-stimulated NO formation in mesangial cells.
  • Quiescent cells were stimulated with either DMEM ( ⁇ ), IL-1 ⁇ (1 nM; +), in the absence or presence of the indicated concentrations of AKH-217, AVX002, or AACOCF3.
  • FIG. 4 shows the effect of the inhibitors of the examples on cytokine-stimulated iNOS protein (A) and mRNA (B) expression and promoter activity in mesangiai cells.
  • Quiescent cells were stimulated with either vehicle (DMEM), IL-1 ⁇ (1 nM), in the absence ( ⁇ ) or presence of the indicated concentrations (in ⁇ M) of AVX001 and AVX002. EtOH, vehicle control.
  • A Cells were taken for protein extraction and equal amount of protein were separated by SDS-PAGE and subjected to a Western blot analysis using a polyclonal antibody against iNOS at a dilution of 1:2000. Data are representative of at least 3 independent experiments giving similar results.
  • FIG. 5 shows the effect of the inhibitors of the examples on [ 3 H]thymidine incorporation in mesangial cells.
  • Quiescent cells were stimulated for 24 h with vehicle (DMEM), or 100 ⁇ M of ATP in the absence ( ⁇ ) or presence of the indicated concentrations of AVX001 or AVX002, in the presence of [ 3 H]thymidine.
  • FIG. 6 shows the effect of the inhibitors of the examples on IL-1 ⁇ -stimulated NF ⁇ B activation in mesangial cells.
  • Quiescent cells were stimulated for 30 min with either vehicle (DMEM), or IL-1 ⁇ (2 nM) in the absence ( ⁇ ) or presence (+) of AVX001 or AVX002 (10 ⁇ M, pretreated 2 h). Thereafter, cell lysates were separated by SDS-PAGE and subjected to a Western blot analysis using a polyclonal antibody against phospho-p65 (NF ⁇ B) (upper panel), HuR as a loading control (middle panel), and I ⁇ B (lower panel). Data in FIG. 6A show duplicates of one representative experiments.
  • FIGS. 6B and C show the densitometric evaluation of NF ⁇ B and I ⁇ B bands.
  • PGE2 formation is highly induced by stimulation of cells with the pro-inflammatory cytokine IL-1 ⁇ . This induction of PGE2 is dose-dependently reduced in the presence of the inhibitors. Maximal effects were seen with 3-10 ⁇ M of AKH-217 (AVX001) and Compound B (AVX002) ( FIG. 1 ).
  • a 2.26 kb fragment of the rat IIA-sPLA2 promoter was cloned according to Scholz-Pedretti et al. (2002). This fragment was ligated into a luciferase-containing vector (pGL3) and used to transfect mesangial cells. As seen in FIG. 2C , the IL-1 ⁇ -stimulated promoter activity was completely reduced by AKH-217.
  • inhibitors of the invention could affect some transcription factors, which are activated by IL-1 ⁇ and are essential for sPLA2 gene transcription.
  • Potential candidates include NF ⁇ B and PPAR.
  • Nitric oxide is also considered a pro-inflammatory mediator which is generated by the inducible NO synthase (iNOS) upon cytokine treatment of mesangial cells.
  • iNOS inducible NO synthase
  • Various previous studies have indicated that iNOS expression is regulated by the same transcription factors as sPLA2.
  • cytokine-triggered iNOS expression is also affected by the inhibitors.
  • NO formation in mesangial cells was highly induced by IL-1 ⁇ treatment. This stimulated NO formation was reduced in a dose-dependent manner in the presence of AKE-217 and AVX002 ( FIG. 3 ). Furthermore, the protein expression of iNOS, which is induced by IL-1 ⁇ ( FIG. 4A ), is down-regulated in the presence of AKH-217 and AVX002 ( FIG. 4A ). A similar reducing effect was also seen on iNOS mRNA expression when quantitative RealTime PCR analyses were performed ( FIG. 4B ). To see whether this effect is due to altered gene transcription of iNOS, luciferase reporter gene assays were performed to measure iNOS promoter activity.
  • Glomerulonephritis is characterized in a first early phase by increased mesangial apoptosis which in a second phase is replaced by an opposite event, i.e. hyperproliferation of mesangial cells.
  • an opposite event i.e. hyperproliferation of mesangial cells.
  • Many previous studies have shown that quiescent mesangial cells in culture can re-enter the cell cycle when exposed to various growth factors, including PDGF, insulin, insulin-like growth factor (IGF), or extracellular nucleotides such as ATP and UTP. These data are confirmed here, as insulin, IGF and ATP trigger increased [ 3 H]thymidine incorporation into DNA ( FIG. 5A and 5B ).
  • FIGS. 5A and 5B Similar data were also obtained when cells were stimulated with PDGF. These data suggest an anti-proliferative potential of the inhibitors.
  • NF ⁇ B activation was measured by Western blot analyses by detecting the amount of phospho-p65 which represents the active transcription factor subunit. Short-term stimulation of cells with IL-1 ⁇ (3 revealed a small but clear increase of phospho-p65 ( FIG. 6 , upper panel) consistent with many previous reports that cytokines activate NF ⁇ B. This effect was reduced by AKH217 ( FIG. 6 ).
  • the inhibitor of ⁇ B which is constitutively expressed in unstimulated cells, is downregulated by IL-1 ⁇ stimulation, and this downregulation is reverted by the inhibitors ( FIG. 6 , lower panel).
  • the nuclear HuR stabilization factor was stained ( FIG. 6 , middle panel)

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