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WO1997045417A1 - Inhibiteurs de production de cytokines, leurs formulations et leur utilisation dans des medicaments et procedes servant a les identifier - Google Patents

Inhibiteurs de production de cytokines, leurs formulations et leur utilisation dans des medicaments et procedes servant a les identifier Download PDF

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Publication number
WO1997045417A1
WO1997045417A1 PCT/GB1997/001415 GB9701415W WO9745417A1 WO 1997045417 A1 WO1997045417 A1 WO 1997045417A1 GB 9701415 W GB9701415 W GB 9701415W WO 9745417 A1 WO9745417 A1 WO 9745417A1
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Prior art keywords
compound
hydro
oxoaldehyde
formula
residue
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Paul Thornalley
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University of Essex Enterprises Ltd
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University of Essex Enterprises Ltd
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Priority to BR9702238A priority Critical patent/BR9702238A/pt
Priority to JP9541830A priority patent/JPH11510521A/ja
Priority to AU29103/97A priority patent/AU2910397A/en
Priority to IL12303397A priority patent/IL123033A0/xx
Priority to EP97923245A priority patent/EP0859762A1/fr
Publication of WO1997045417A1 publication Critical patent/WO1997045417A1/fr
Priority to NO980299A priority patent/NO980299L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to cytokine production inhibitors, particularly antagonists to certain non-enzymatically-modif led proteins, and more particularly to their pharmacological activity and therapeutic effect especially in the form of a pharmaceutical formulation.
  • the non-enzymatic modification of proteins by saccha ⁇ des, non-enzymatic glycosylation or glycation is known to occur in physiological systems.
  • glucose reacts non-enzyma 11 cal 1 y under physiological conditions with lysine residue side chain- and N-termmal ammo groups in proteins to form a Schiff ' s base which undergoes an Amadori rearrangement to form N-( 1 -deoxy-D-f ructos-1 -yl )-am ⁇ no acid residues or f ructosamines .
  • These f ructosamines undergo further reaction and slowly degrade to form advanced glycation end-products.
  • phagocylic cells such as macrophages , monocytes, Kuppfer cells or glial cells
  • This process also stimulates monocyte chemotaxis; transendothel lal movement and proliferation of macrophages; chemotaxis and angiogenesis of human endothelial cells; and the synthesis and secretion of pro-inflammatory cytokines and growth factors.
  • retinopathy retinopathy , neuropathy and nephropathy
  • diabetes mellitus retinopathy , neuropathy and nephropathy
  • diabetic embryopathy retinopathy , neuropathy and nephropathy
  • amyloidosis associated with Alzheimer's disease and chronic renal dialysis.
  • arginine residues are major sites of irreversible modification in glycated proteins and that the physiological modifying agents are reactive ⁇ -oxoaldehydes (RCOCHO) which are present in physiological systems.
  • RCOCHO reactive ⁇ -oxoaldehydes
  • ⁇ -oxoaldehydes are formed from the degradation of Amadori products and elsewhere (such as from the metabolism of ketone bodies, by catabolism of threonine or by lipid peroxidation) .
  • Preferred ⁇ -oxoaldehydes are wherein R is H, C-
  • Examples are: methylglyoxal MeCOCHO; pentosone HOCH 2 (CHOH) 2 COCHO; glyoxal (CH0) 2 ; 3-deox ⁇ pentosone HOCH 2 -CHOH-CH 2 COCHO; 3-deoxyglucosone H0CH 2 (CHOH ) 2 CH 2 COCHO; and glucosone HOCH 2 (CHOH) 3COCHO.
  • modified arginine residues provide the receptor recognition factor for the binding of modified proteins to phagocytic cells and provide the pharmacophoric group for the induction - -
  • cytokines ⁇ nterleuk ⁇ n-1 ⁇ (IL-1B), macrophage colony stimulating factor (MCSF) and tumour necrosis factor- ⁇ (TNF ⁇ ) . Therefore, any compounds or ligands which inhibit the binding of such modified proteins to cell surface receptors such as those on human monocytes and/or which inhibit production of such cytokines will be useful in the treatment or prevention of the development of diseases or pathologies in which cytokines specifically or such modified arginine residues generally have a role.
  • IL-1B ⁇ nterleuk ⁇ n-1 ⁇
  • MCSF macrophage colony stimulating factor
  • TNF ⁇ tumour necrosis factor- ⁇
  • the present invention therefore provides a method of identifying a compound suitable for use in the treatment or prevention of a medical condition arising from the synthesis or secretion of a cytokine, which method comprises:
  • the present invention therefore further provides an antagonist to an ⁇ -oxoaldehyde-modified arginine residue.
  • the present invention provides an antagonist to a glyoxal or methylglyoxal-modified arginine residue.
  • the present invention provides an antagonist to a protein which comprises an arginine residue modified by an ⁇ -oxoaldehyde and which - -
  • cytokines either (a) binds to receptors on phagocytes and/or (b) provides the pharmacophore which triggers the synthesis and/or secretion of cytokines.
  • Chem. Abs . 115 8662f discloses certain lminohydantoms of formula (A) as being tested for anticonvulsant activity:
  • the present invention provides an antagonist to an ⁇ -oxoaldehyde-modi f ied arginine residue of formula (B):
  • R is as defined above.
  • R is 2,3,4- trihydroxybutyl , H or methyl, more preferably H or methyl.
  • R is methyl, namely, a 2-am ⁇ no-5- ( 2-am ⁇ no-5-hydro-5-methylim ⁇ dazol- 4-on-2-yl) pentanoic acid residue or an N ⁇ -( 5-hydro-5- methyl-4-imidazolon-2-yl ) ornithine residue.
  • the present invention further provides a 2, 5-substituted-2-amino-5-hydro-imidazol-4-one other than those of formula (A) above.
  • the present invention provides a compound of formula (I):
  • is an aryl or alkyl group
  • R 2 is a hydrogen atom
  • R3 and R4 are each independently selected from a hydrogen atom, and aryl and alkyl groups; including salts, esters or hydrated forms thereof, provided that when R ⁇ is methyl, then either R3 is other than H or Ph, or R ⁇ is other than H, Ph, CH 2 Ph or CH 2 CH(CH 3 ) 2 .
  • aryl may be substituted or unsubstituted and are preferably phenyl or phenylalkyl such as benzyl or phenylethyl.
  • Alkyl groups may be substituted or unsubstituted, straight or branched chain or cyclic and are preferably C- j _g alkyl, more preferably C ⁇ _4 alkyl such as methyl, ethyl, n- or iso- propyl, n- , iso- or sec-butyl, cyclopropyl or cyclobutyl.
  • the groups are preferably unsubstituted or substituted by mildly hydrophobic radicals such as halo such as bromo.
  • aryl groups include p- bromophenyl or fluorophenyl.
  • the groups may be substituted by amino, acylamino such as alkylcarbonylamino, carboxyl or alkyloxycarbonyl .
  • alkyl groups include 4-ace tarn 1 do- 4- alkoxycarbonyl butyl groups.
  • R ⁇ _4 is or are aryl. More preferably, R3 corresponds to R as defined with respect to the ⁇ -oxoaldehyde and R4 is H.
  • the compounds of formula (I) can exist in three isomeric forms, each of which is encompassed by the present invention.
  • the compounds of formula (I) may be prepared by reacting the corresponding guanidino derivative with the corresponding ⁇ -oxoaldehyde of formula RCOCHO
  • ⁇ -oxoaldehydes glyoxal, methylglyoxal and 3-deoxyglucosone is increased in diabetes mellitus and has been linked to the development of chronic pathologies in diabetes (such as neuropathy, retinopathy, nephropathy) and embryonic malformations in diabetic pregnancy.
  • the formation of glyoxal is also increased in alcohol intoxication and the formation of methylglyoxal is also increased in starvation.
  • Methylglyoxal-modif ied proteins are also present in amyloid deposits associated with chronic renal dialysis and central neuropathies such as Alzheimer's disease.
  • Methylglyoxal-modif ied proteins are normally degraded and modified arginine residues excreted in the urine; these may, however, accumulate in renal insufficiency.
  • Diseases or pathologies m which the compounds or antagonists of the present invention are particularly useful are therefore: cataract, retinopathy, peripheral neuropathy, nephropathy and embryopathy in diabetes mellitus, coronary heart disease, chronic renal insufficiency, central neuropathies such as Alzheimer's disease, hepatitis and dementia associated with chronic alcohol intoxication, and inflammation and wasting associated with anorexia.
  • cytokines IL- 1 ⁇ , M-CSF and TNF ⁇ are increased formation and secretion of the cytokines IL- 1 ⁇ , M-CSF and TNF ⁇ by monocytes/ macrophages and endothelial cells in response to modified arginine residues of ⁇ -oxoaldehyde-modif ied proteins m .
  • vivo is expected to have a role in, for example: atherosclerosis associated with macrovascular disease; glomerulosclerosis associated with nephropathy; microang I opathy associated with retinopathy and peripheral neuropathy; and cytokine-mediated cytotoxicity associated with hepatitis and central neuropathies .
  • the present invention further provides an antagonist as described hereinbefore, in particular, a 2, 5-subst ⁇ tuted-2-am ⁇ no-5-hydro ⁇ m ⁇ dazol-4-one including those of formula (A) above for use in the treatment or prevention of any of the pathologies or diseases mentioned above.
  • an antagonist as described hereinbefore especially a compound of formula (I), including those also of formula (A), for treating patients with diabetes mellitus and/or Alzheimer's disease.
  • the present invention provides the use of an antagonist as described hereinbefore, such as -
  • a compound of formula (I) including those also of formula (A), for the preparation of a medicament for treating or preventing those pathologies or diseases.
  • the present invention therefore also provides a pharmaceutical formulation comprising an antagonist as described hereinbefore, such as a compound of formula (I), in association with a pharmaceutically acceptable carrier therefor and the use of such formulations in the treatment or prevention of the aforementioned pathologies or diseases.
  • Suitable formulations are well-known to those skilled m the art and include: tablets, capsules, mjectables (whether for intravenous, intramuscular, intraperitoneal or transdermal administration, or the like), suspensions, solutions, creams, powders, and the like.
  • the formulation is suitable for oral administration such as tablets and capsules, or for injection such as intravenous or intramuscular injection.
  • the present invention therefore further provides a method for preparing a pharmaceutical formulation which method comprises bringing into intimate physical admixture an antagonist as described hereinbefore such as a compound of formula (I) together with a pharmaceutically acceptable carrier therefor.
  • Suitable doses can be determined by those skilled in the art and depend upon the particular compound to be administered, the condition to be treated and the patient concerned. However, a suitable dose may fall in the range 0.1-1 mg/kg per dose, preferably administered in from one to four doses per week.
  • HSA human serum albumin
  • MG m ⁇ n -HSA HSA minimally-modified with methylglyoxal - -
  • N ⁇ -acetyl-Ng-( 5-hydro-5-methyl ⁇ m ⁇ dazol-4-on-2-yl ) ornithine was prepared by incubation of N Q - acetylarginme (16.7 mM) and methylglyoxal (20 mM) in sodium phosphate buffer (200 mM, pH 7.4) for 7 days at 37°C, then lyophilized to dryness . The residue was extracted with methanol (50ml ) ; the methanol was removed 1n vacuo and the residual solid product purified by reversed phase HPLC .
  • the column was Nova- PakTM octadecylsilica (ODS) cartridge (2.5 cm x 10 cm) fitted with a pre-column (2.5 cm x 1 cm) in a Waters 25 x 10 radial compression unit.
  • the mobile phase was 500 mM potassium phosphate buffer, pH 7.4, the flow rate 9.9 ml/nun, the sample was 10 mg in 0.1 ml of mobile phase, and the eluate absorbance was monitored at 225 nm.
  • a major peak was collected of retention time 5.7 mm, lyophilized, extracted with methanol ( 1 x 40 ml; 2 x 20 ml) and the methanol removed ⁇ _n vacuo to yield the product.
  • Ethylguanidine sulphate (1 mmol, 272 mg) and methylglyoxal (1 mmol, 72 mg ) were dissolved in 1 OOmM sodium phosphate buffer, pH 7.4 (10 ml), and stirred at room temperature ( 18°C) for 4 days and a further 1 day at 37°C.
  • the product mixture was lyophilised and the residual solid extracted with methanol (4 x 20 ml). Methanol was removed from the combined extracts and the solid dried to constant weight in a vacuum dessicator.
  • Ethylguanidine sulphate ( 1 mmol, 272mg) and pheny lgl y oxa 1 monohydrate (1 mmol, 152 mg ) were dissolved in 50mM sodium phosphate buffer, pH 7.4 , in 50% methanol (10 ml), and stirred at room temperature (18°C) for 4 days and a further 1 day at 37°C.
  • the product was lyophilised and the residual solid extracted with methanol (4 x 20 ml) . Methanol was removed from the combined extracts and the solid dried to constant weight in a vacuum dessicator.
  • MG m ⁇ n -HSA was prepared by incubation of HSA (100 ⁇ M ) in sodium phosphate buffer (100 mM at pH 7.4 and 37°C) with 0.5 mM high purity methylglyoxal for 24 hours, dialysed against ammonium bicarbonate buffer (30 mM at pH 7.9 and 4°C) and lyophilized to dryness.
  • the extent of modification was determined by preparation of MG m ⁇ n -HSA with 2-[ C Jmethylglyoxal , with assay of specific radioactivity content in the dialyzed protein by scintillation counting and assay for protein by the Lowry method using the unmodified protein as standard. This indicated the presence of 2.4 ⁇ 0.3 methylglyoxal residues per molecule of MG m ⁇ n - HSA.
  • M-CSF macrophage colony stimulating factor
  • TNF ⁇ tumour necrosis factor ⁇
  • IL-1B ⁇ nterleuk ⁇ n-1 ⁇
  • Example 8 Preparation of human prothrombin minimally- modified by methyl glyoxal (MG rn ⁇ n ⁇ Pr)
  • Human prothrombin minimally-modified by methylglyoxal (MG m ⁇ n -Pr) was prepared by incubation of human prothrombin (100 ⁇ M ) in sodium phosphate buffer (100 mM, pH 7.4 and 37°C) with 500 ⁇ M methylglyoxal for 24 h.
  • the modified protein was then dialyzed against ammonium bicarbonate buffer (30 mM, pH 7.9 and 4°C) and lyophilized to dryness.
  • Human transferrin minimally-modified by methylglyoxal (MG m ⁇ n -Tr) was prepared by incubation of human transferrin (100 ⁇ M ) in sodium phosphate buffer (100 ⁇ M, pH 7.4 and 37°C) with 500 ⁇ M methylglyoxal for 24 h.
  • the modified protein was then dialyzed against ammonium bicarbonate buffer (30 mM, pH 7.9 and 4°C) and lyophilized to dryness.
  • Example 10- Binding of human serum albumin modified by methylglyoxal (MG m ⁇ n -HSA) to human THP-1 monocvtic cells and displacement by N ⁇ -Acety1-N ⁇ - ( 5-hydro-5- methyl-4- ⁇ m ⁇ dazolon-2-y3 )orn ⁇ thine THP-1 cells (2 x IO 6 ) were incubated in a culture medium of RPMI 1640 with 3% (w/v) human serum albumin (HSA) with [ 125 I]MG rn ⁇ n -HSA at 4°C, total volume 100 ⁇ l.
  • MG m ⁇ n -HSA methylglyoxal
  • MG rn ⁇ n -HSA was prepared according to the method of
  • Example 11 Inhibition of advanced glycated protein- induced ⁇ nterleukm-1 ⁇ secretion of human monocvtic THP-1 cells in vitro by 2-am ⁇ noe t hy 1- 5-hydro- 5- methyl ⁇ m ⁇ dazol-4-one and 4- ( N , 2-am ⁇ no-5-hydro-5- methyl ⁇ m ⁇ dazol-4-on-2-yl )benzo ⁇ c acid
  • Human serum albumin minimally-modified by methylglyoxal (MG m ⁇ n -HSA) was prepared by incubation of human serum albumin (6.6 mg/ml) in sodium phosphate buffer ( 100 mM, pH 7.4 and 37°C) with 0.5 mM methylglyoxal for 24 h.
  • the solution of MG m ⁇ n -HSA was - -
  • THP-1 cells 5 x 10 cells/ml, were incubated for 24 h in RPMI 1640 medium containing 20% foetal calf serum under an atmosphere of 5% C0 2 in air with 100% humidity with 20 ⁇ M MG m ⁇ n -HSA and 0-10 ⁇ M 2-am ⁇ noethyl- 5-hydro-5-methyl ⁇ m ⁇ dazol-4-one and 4- (N, 2-amino-5- hydro-5-methyl ⁇ m ⁇ dazol-4-on-2-yl ) benzoic acid. The cells were then sedimented by centrifugation and the supernatant removed and assayed for IL-1 ⁇ by ELISA.
  • the median inhibitory concentration EC Q values were: 2-am ⁇ noethyl-5-hydro-5-methyl ⁇ midazol-4-one 0.37 ⁇ M and 4-(N, 2-am ⁇ no-5-hydro-5-methyl ⁇ midazol-4-on-2-yl)benzoic
  • Example 12 Inhibition of advanced glycated protein- induced macrophage-colony stimulating factor secretion of human monocytes in vitro by 2-aminoethyl-5-hydro-5- methy 1 imidazol-4-one and 4- ( N , 2-am ⁇ no-5 ⁇ hydro-5- methylimidazol-4-on-2-yl )benzo ⁇ c acid
  • Human monocytes were isolated from venous human blood (50 ml) collected with sterile acid-ci trate- dextrose anticoagulant. The red blood cells were allowed to sediment and the leukocytes collected from the leukocyte-rich plasma by centrif ugation (200g, 15 min). Leukocytes were re-suspended in RMPI 1640 medium (4 ml), layered on Ficoll-Hypaque 1077 (4 ml) and centrifuged (400g, 30 min). The mononuclear layer at the interface was removed, washed with RPMI 1640 and re-suspended in RPMI 1640 at a density of 2 x 10 6 cells/ml.
  • the monocytes were incubated with MG m ⁇ n -HSA and compounds for 24 h.
  • concentration of M-CSF in the extracellular medium was assayed by removal of the culture medium from the wells, centrifugation of the medium (200g, 15 min) to sediment suspended cells and assy of the supernatant for M-CSF by ELISA.
  • the median inhibitory cencentration EC ⁇ Q values were 2-am ⁇ noethyl- 5-hydro-methyl ⁇ m ⁇ dazol-4-one 7.6 ⁇ M and 4-(N, 2-am ⁇ no-5- hydro-5-methyl ⁇ m ⁇ dazol-4-on-2-tl)benzo ⁇ c acid 64 nM.

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Abstract

Composés ou ligands inhibant la fixation de résidus d'arginine modifiée par α-oxoaldéhyde et représentés par la formule (I) dans laquelle R1 représente un groupe aryle ou alkyle; R2 représente un atome d'hydrogène; R3 et R4 sont chacun indépendamment sélectionnés dans un atome d'hydrogène, des groupes aryle et des groupes alkyle; y compris leurs sels, esters ou formes hydratées. Ces composés peuvent être formulés en association avec un véhicule pharmaceutique approprié et utilisés dans le traitement ou dans la prévention de complications cliniques chroniques associées au diabète sucré, de la macroangiopathie et de l'amylose associée à la maladie d'Alzheimer et à la dialyse rénale chronique. L'invention concerne également certains résidus d'arginine modifiés par α-oxoaldéhyde, ainsi que leur utilisation dans un procédé d'analyse de composés afin de rechercher leur efficacité thérapeutique.
PCT/GB1997/001415 1996-05-25 1997-05-23 Inhibiteurs de production de cytokines, leurs formulations et leur utilisation dans des medicaments et procedes servant a les identifier Ceased WO1997045417A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR9702238A BR9702238A (pt) 1996-05-25 1997-05-23 Uso de um composto composto para uso no tratamento ou prenvenção de uma doença ou patologia envolvendo a produção de citocinas formulação farmacêutica processos de identificaç o de um composto de preparação de um composto e de tratamento ou prevenção de uma doença ou patologia envolvendo uma citocina e composto ou ligando para uso no processo de identificação
JP9541830A JPH11510521A (ja) 1996-05-25 1997-05-23 サイトカイン産生阻害剤、その調合および薬剤への使用法、ならびにその同定法
AU29103/97A AU2910397A (en) 1996-05-25 1997-05-23 Cytokine production inhibitors, formulations thereof and their use in medicine, and methods for their identification
IL12303397A IL123033A0 (en) 1996-05-25 1997-05-23 Cytokine production inhibitors formulations thereof and their use in medicine and methods for their identification
EP97923245A EP0859762A1 (fr) 1996-05-25 1997-05-23 Inhibiteurs de production de cytokines, leurs formulations et leur utilisation dans des medicaments et procedes servant a les identifier
NO980299A NO980299L (no) 1996-05-25 1998-01-23 Cytokinproduksjonsinhibitorer, preparater derav og deres anvendelse i medisin, samt fremgangsmåter for deres identifikasjon

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GBGB9611046.5A GB9611046D0 (en) 1996-05-25 1996-05-25 Pharmacological compounds
GB9611046.5 1996-05-25

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WO1997045417A1 true WO1997045417A1 (fr) 1997-12-04

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EP (1) EP0859762A1 (fr)
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US7417047B2 (en) 2005-06-30 2008-08-26 Wyeth Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7423158B2 (en) 2005-09-26 2008-09-09 Wyeth Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase
US7456186B2 (en) 2004-06-16 2008-11-25 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7482349B2 (en) 2004-06-16 2009-01-27 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US7488832B2 (en) 2005-02-14 2009-02-10 Wyeth Azolylacylguanidines as β-secretase inhibitors
US7563796B2 (en) 2005-01-14 2009-07-21 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7582667B2 (en) 2006-02-24 2009-09-01 Wyeth Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase
US7700606B2 (en) 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
US7723368B2 (en) 2007-03-23 2010-05-25 Wyeth Llc Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase
US7732457B2 (en) 2005-02-01 2010-06-08 Wyeth Llc Amino-pyridines as inhibitors of β-secretase
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7973067B2 (en) 2003-12-15 2011-07-05 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8093254B2 (en) 2006-12-12 2012-01-10 Schering Corporation Aspartyl protease inhibitors
US8178513B2 (en) 2003-12-15 2012-05-15 Schering Corporation Heterocyclic aspartyl protease inhibitors

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US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8937093B2 (en) 2003-12-15 2015-01-20 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
US8242112B2 (en) 2003-12-15 2012-08-14 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8178513B2 (en) 2003-12-15 2012-05-15 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7973067B2 (en) 2003-12-15 2011-07-05 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7700602B2 (en) 2004-06-16 2010-04-20 Wyeth Llc Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US7482349B2 (en) 2004-06-16 2009-01-27 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US7456186B2 (en) 2004-06-16 2008-11-25 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7563796B2 (en) 2005-01-14 2009-07-21 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7732457B2 (en) 2005-02-01 2010-06-08 Wyeth Llc Amino-pyridines as inhibitors of β-secretase
US7488832B2 (en) 2005-02-14 2009-02-10 Wyeth Azolylacylguanidines as β-secretase inhibitors
US7417047B2 (en) 2005-06-30 2008-08-26 Wyeth Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7705030B2 (en) 2005-06-30 2010-04-27 Wyeth Llc Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7423158B2 (en) 2005-09-26 2008-09-09 Wyeth Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase
US7582667B2 (en) 2006-02-24 2009-09-01 Wyeth Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase
US7700606B2 (en) 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
US8093254B2 (en) 2006-12-12 2012-01-10 Schering Corporation Aspartyl protease inhibitors
US7723368B2 (en) 2007-03-23 2010-05-25 Wyeth Llc Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase

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AU2910397A (en) 1998-01-05
NO980299D0 (no) 1998-01-23
GB9611046D0 (en) 1996-07-31
CA2227811A1 (fr) 1997-12-04
MX9800670A (es) 1998-09-30
NO980299L (no) 1998-03-24
HUP9902796A3 (en) 2000-07-28
HUP9902796A2 (hu) 2000-04-28
JPH11510521A (ja) 1999-09-14
EP0859762A1 (fr) 1998-08-26
BR9702238A (pt) 1999-07-27
IL123033A0 (en) 1998-09-24

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