EP2117540A1 - New use of glutaminyl cyclase inhibitors - Google Patents

New use of glutaminyl cyclase inhibitors

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Publication number
EP2117540A1
EP2117540A1 EP08717208A EP08717208A EP2117540A1 EP 2117540 A1 EP2117540 A1 EP 2117540A1 EP 08717208 A EP08717208 A EP 08717208A EP 08717208 A EP08717208 A EP 08717208A EP 2117540 A1 EP2117540 A1 EP 2117540A1
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EP
European Patent Office
Prior art keywords
inhibitor
inhibitors
mcp
compound
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08717208A
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German (de)
English (en)
French (fr)
Inventor
Stephan Schilling
Holger Cynis
Torsten Hoffmann
Hans-Ulrich Demuth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vivoryon Therapeutics AG
Original Assignee
Probiodrug AG
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Priority claimed from US11/685,881 external-priority patent/US7732162B2/en
Application filed by Probiodrug AG filed Critical Probiodrug AG
Priority to EP11192085A priority Critical patent/EP2481408A3/en
Publication of EP2117540A1 publication Critical patent/EP2117540A1/en
Withdrawn legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
    • 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
    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates in general to an inhibitor of a glutaminyl peptide cyclotransferase, and the use thereof for the treatment and/or prevention of a disease or disorder selected from the group consisting of rheumatoid arthritis, atherosclerosis, restenosis, lung fibrosis, liver fibrosis, renal fibrosis, pancreatitis, mild cognitive impairment, Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, neuropathic pain, graft rejection/graft failure/graft vasculopathy, hypertension, HIV infections/AIDS, gestosis, cancer/hemangioendothelioma proliferation, tuberous sclerosis, and gastric carcinomas.
  • a disease or disorder selected from the group consisting of rheumatoid arthritis, atherosclerosis, restenosis, lung fibrosis, liver fibrosis, renal fibrosis, pancreatitis, mild cognitive impairment, Alzheimer
  • the present invention pertains to diagnostic kits and methods based on the use of a glutaminyl cyclase inhibitor.
  • Glutaminyl cyclase catalyzes the intramolecular cyclization of N-terminal glutaminyl residues into pyroglutamic acid (5-oxo-proline, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamyl residues into pyroglutamic acid under liberation of water.
  • EP 02 011 349.4 discloses polynucleotides encoding insect glutaminyl cyclase, as well as polypeptides encoded thereby.
  • This application further provides host cells comprising expression vectors comprising polynucleotides of the invention. Isolated polypeptides and host cells comprising insect QC are useful in methods of screening for agents that reduce glutaminyl cyclase activity. Such agents are described as useful as pesticides .
  • Chemotactic cytokines are proteins that attract and activate leukocytes and are thought to play a fundamental role in inflammation. Chemokines are divided into four groups categorized by the appearance of N-terminal cysteine residues
  • CXC CXC-chemokines
  • CXC CXC-chemokines preferentially act on neutrophils.
  • CC CXC-chemokines attract preferentially monocytes to sites of inflammation.
  • Monocyte infiltration is considered to be a key event in a number of disease conditions (Gerard, C. and Rollins, B. J.
  • MCP-1-4 The MCP family, as one family of chemokines, consists of four members (MCP-1-4), displaying a preference for attracting monocytes but showing differences in their potential (Luini, W., et al . , (1994) Cytokine 6, 28-31; Uguccioni, M., et al . , (1995) Eur J Immunol 25, 64-68) .
  • MCP-1-4 cDNA as well as amino acid sequences of MCP-1-4 are indicated:
  • Liver Physiol 288, G1259-G1265) Liver Physiol 288, G1259-G1265) ; Alzheimer's disease (Yamamoto, M., et al . , (2005) Am. J Pathol. 166, 1475-1485); lung fibrosis (Inoshima, I., et al . , (2004) Am. J Physiol Lung Cell MoI. Physiol 286, L1038-L1044) ; renal fibrosis (Wada, T., et al., (2004) J Am. Soc .Nephrol . 15, 940-
  • MCP-I might also play a role in gestosis (Katabuchi, H., et al . ,
  • the mature form of human and rodent MCP-I is posttranslationally modified by Glutaminyl Cyclase (QC) to possess an N-terminal pyroglutamyl (pGlu) residue.
  • QC Glutaminyl Cyclase
  • pGlu N-terminal pyroglutamyl
  • the N-terminal pGlu modification makes the protein resistant against N-terminal degradation by aminopeptidases, which is of importance, since chemotactic potency of MCP-I is mediated by its N-terminus (Van Damme, J., et al., (1999) Chem Immunol 72, 42-56).
  • Artificial elongation or degradation leads to a loss of function although MCP-I still binds to its receptor (CCR2) (Proost, P., et al .
  • Inhibitors of Glutaminyl Cyclase are small orally available compounds, which target the important step of pGlu-formation at the N-terminus of MCP-I (Cynis, H., et al . , (2006) Blochlm.Blophys .Acta 1764, 1618-1625; Buchholz, M., et al . , (2006) J Med Chem 49, 664-677).
  • the N-terminus of MCP- 1 is not protected by a pGlu-residue .
  • the N-terminus possesses a glutamine-proline motif, which is prone to cleavage by dipeptidylpeptidases, e.g. dipeptidylpeptidase 4 and fibroblast activating protein (FAP, Seprase) , which are abundant on the endothelium and within the blood circulation.
  • dipeptidylpeptidases e.g. dipeptidylpeptidase 4 and fibroblast activating protein (FAP, Seprase)
  • FAP fibroblast activating protein
  • Atherosclerotic lesions which limit or obstruct coronary blood flow, are the major cause of ischemic heart disease related mortality, resulting in 500,000 - 600,000 deaths annually.
  • Percutaneous transluminal coronary angioplasty (PTCA) to open the obstructed artery was performed in over 550,000 patients in the U.S. and 945,000+ patients worldwide in 1996 (Lemaitre et al . , 1996) .
  • a major limitation of this technique is the problem of post-PTCA closure of the vessel, both immediately after PTCA
  • acute occlusion and in the long term (restenosis) : 30% of patients with subtotal lesions and 50% of patients with chronic total lesions will progress to restenosis after angioplasty. Additionally, restenosis is a significant problem in patients undergoing saphenous vein bypass graft.
  • the mechanism of acute occlusion appears to involve several factors and may result from vascular recoil with resultant closure of the artery and/or deposition of blood platelets along the damaged length of the newly opened blood vessel followed by formation of a fibrin/red blood cell thrombus.
  • Restenosis after angioplasty is a more gradual process and involves initial formation of a subcritical thrombosis with release from adherent platelets of cell derived growth factors with subsequent proliferation of intimal smooth muscle cells and local infiltration of inflammatory cells contributing to vascular hyperplasia. It is important to note that multiple processes, among those thrombosis, cell proliferation, cell migration and inflammation each seem to contribute to the restenotic process.
  • a 30-50% restenosis rate translates to 120,000 - 200,000 U.S. patients at risk from restenosis. If only 80% of such patients elect repeated angioplasty (with the remaining 20% electing coronary artery bypass graft) and this is added to the costs of coronary artery bypass graft for the remaining 20%, the total costs for restenosis tretment easily amounts to billions of dollars in the U.S.. Thus, successful prevention of restenosis could result not only in significant therapeutic benefit but also in significant health care savings.
  • Monocyte chemoattractant protein 1 (MCP-I, CCL2) belongs to a family of potent chemotactic cytokines (CC chemokines) , that regulate the trafficking of leukocytes, especially monocytes, macrophages and T-cells, to sites of inflammation (Charo,I.F. and Taubman,M.B. (2004) Circ.Res. 95, 858-866). Besides its role in, e.g. vascular disease, compelling evidence points to a role of MCP-I in Alzheimer's disease (AD) (Xia,M.Q. and Hyman,B.T.
  • AD Alzheimer's disease
  • Amyloid- ⁇ protein (A ⁇ ) induces chemokine secretion in vitro
  • activated microglia also phagocytose A ⁇ peptides leading to an amplified activation (Rogers, J. and Lue,L.F. (2001) Neurochem. Int . 39, 333-340) .
  • MCP-I shows an increased level in serum of patients with MCI and early AD (Clerici,F., et al . , (2006) Neurobiol .Aging 27, 1763-1768).
  • the present invention relates to inhibitors of a glutaminyl peptide cyclotransferase and the use thereof for the treatment and/or prevention of a disease or disorder selected from the group consisting of inflammatory diseases selected from a. neurodegenerative diseases, e.g. mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British
  • a disease or disorder selected from the group consisting of inflammatory diseases selected from a. neurodegenerative diseases, e.g. mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British
  • Dementia Familial Danish Dementia, multiple sclerosis, b. chronic and acute inflammations, e.g. rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, c. fibrosis, e.g. lung fibrosis, liver fibrosis, renal fibrosis, d. cancer, e.g. cancer/hemangioendothelioma proliferation, gastric carcinomas, e. metabolic diseases, e.g. hypertension, f . and other inflammatory diseases, e.g. neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis.
  • chronic and acute inflammations e.g. rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis
  • c. fibrosis e.g. lung fibrosis, liver fibrosis, renal fibrosis
  • cancer
  • Figure 1 shows the incubation of MCP-IM -76 ) bearing an N- terminal glutaminyl (A) or Pyroglutamyl (5-oxo-L-Prolyl) residue (B) with recombinant human DP4 for 24 h.
  • A N- terminal glutaminyl
  • B Pyroglutamyl (5-oxo-L-Prolyl) residue
  • FIG. 2 shows the incubation of MCP-I ( i- ⁇ Q) bearing an N- terminal glutaminyl (A) or Pyroglutamyl (5-oxo-L-Prolyl) residue with human synovial fibroblast MMP-I for 24 h.
  • MCP-I N-terminal glutamine
  • A N-terminal glutaminyl
  • Pyroglutamyl 5-oxo-L-Prolyl
  • Figure 3 shows the incubation of MCP-I ( i- ⁇ Q) carrying an N- terminal glutaminyl (A) or Pyroglutamyl (5-oxo-L-Prolyl) with human synovial fibroblast MMP-I and recombinant human DP4 for 24 h.
  • MCP-I was incubated with recombinant human QC 3 h prior to assay start.
  • Resulting MMP-I cleavage products were analyzed after 0 min, 15 min, 30 min, Ih, 2h, 4h and 24 h using Maldi-TOF mass spectrometry
  • Figure 4 shows the isolation of human MCP-I from human neuroblastoma cell line SH-SY5Y.
  • M DNA standard in bp; 1: full length human MCP-I isolated from SH-SY5Y
  • Figure 5 shows the nucleotide (A) and amino acid (B) alignment of human MCP-I isolated from SH-SY5Y (upper lane) and human MCP- 1 genebank accession M24545 (lower lane) . Single nucleotide polymorphism is depicted in bold.
  • C shows the concentration of human MCP-I ( i- ⁇ Q) (WT) and mutant human MCP-I lacking the N- terminal pGlu residue ( ⁇ Q1) in the supernatant of transfected HEK293 cells in comparison to vector transfected control (pcDNA) .
  • Figure 6 A shows the concentration of human MCP-IM -76 ) (WT) and mutant human MCP-I lacking the two N-terminal amino acids
  • Figure 7 A shows the concentration of human MCP-I (1-76) (WT) in the supernatant of transfected HEK293 cells in absence and presence of 10 ⁇ M 1- (3- (lH-imidazol-1-yl) propyl) -3- (3, 4- dimethoxyphenyl) thiourea hydrochloride in comparison to vector transfected control (pcDNA) .
  • Figure 8 shows the quantification of the vascular remodeling of the cuffed vessel wall segments of untreated ApoE3 Leiden mice
  • vascular circumference i.e. the total area within the outer diameter of the vessel segment and the remaining lumen (B) in ⁇ m ⁇ .
  • Figure 9 shows the quantification of the vascular remodeling of the cuffed vessel wall segments of untreated ApoE3 Leiden mice (black bars) or mice treated with (open bars) 1- (3- (lH-imidazol- 1-yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydro-chloride .
  • Mice were sacrificed 14 days after cuff placement. Expressed is the lumen stenosis A in % and the area of neointima B in ⁇ m ⁇ . (*, P ⁇ 0.05, Student's t-test) .
  • Figure 10 shows the quantification of the vascular remodeling of the cuffed vessel wall segments of untreated ApoE3 Leiden mice (black bars) or mice, which were treated with (open bars) of 1- (3- (lH-imidazol-1-yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydrochloride. Mice were sacrificed 14 days after cuff placement. Expressed is the area of the media A in ⁇ m ⁇ and the intima / media ratio B. (*, P ⁇ 0.05, Student's t-test).
  • Figure 11 shows adhering and infiltrating cells per cross section in absence (black bars) or presence (open bars) of 1- (3- ( lH-imidazol-1-yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydrochloride treatment.
  • Total number of adhering cells per cross section was counted in the cross section of the cuffed femoral arteries harvested two days after cuff placement.
  • a specific staining for monocytes/macrophages was used to identify the adhering and infiltrating monocytes. (*, P ⁇ 0.05, Student's t-test).
  • Figure 12 shows examples of MCP-I staining by immunohistochemistry of lesions at the early time point (2 days) and the late time point (14 days) in untreated mice (control) and mice, which were treated with 1- (3- (lH-imidazol-1- yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydrochloride .
  • Figure 13 shows the quantification of MCP-I staining in cross sections of mice sacrificed after 2 days (early time point) A or after 14 days (late time point) B within the media and neointima in absence (black bars) and presence (open bars) of 1-(3-(1H- imidazol-1-yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydrochloride treatment. (*, P ⁇ 0.05; Student's t-test).
  • Figure 14 shows the relative amount of MCP-I staining (%) in cross sections of mice sacrificed after 2 days (early time point) (A) or after 14 days (late time point) (B) within the media and neointima in absence (black bars) and presence (open bars) of 1- (3- (lH-imidazol-1-yl) propyl) -3- (3, 4- dimethoxyphenyl) thiourea hydrochloride treatment. (*, P ⁇ 0.05; Student' s t-test) .
  • Figure 15 shows the quantification of the accelerated atherosclerosis in the vessel wall based on the quantification of monocyte/macrophage staining using marker AIA31240.
  • FIG. 15 shows the quantification of the accelerated atherosclerosis in the vessel wall based on the quantification of monocyte/macrophage staining using marker AIA31240.
  • Foam cell accumulation is illustrated as (A) foam cell positive area / cross section in % and (B) foam cell positive area / cross section in ⁇ m 2 .
  • Figure 16 illustrates cleavage of human MCP-I ( i- ⁇ Q) bearing an N-terminal glutaminyl (A) or pyroglutamyl (5-oxo-L-Prolyl) residue (B) by recombinant human Aminopeptidase P for 24 h.
  • the pyroglutamate formation at the N-Terminus was accomplished by incubation of MCP-I with recombinant human QC for 3 h prior to the assay.
  • the DP4 cleavage products were analyzed after 0 min, 15 min, 30 min, Ih, 2h, 4h and 24 h using Maldi-TOF mass spectrometry.
  • Figure 17 illustrates the cleavage of human MCP-I ( i-76 ) bearing an N-terminal glutaminyl (A) or pyroglutamyl (5-oxo-L-Prolyl) residue (B) by recombinant human DP4 for 4 h.
  • the pyroglutamate formation at the N-Terminus was accomplished by incubation of MCP-I with recombinant human QC for 3 h prior to assay.
  • Figure 18 shows the degradation of human MCP-IM -76 ) carrying an N-terminal glutaminyl residue (A) or pyroglutamyl (5-oxo-L- Prolyl) residue (B) in human serum for 7 and 24 h, respectively.
  • MCP-I was incubated with recombinant human QC for 3 h prior to assay start.
  • Gln 1 -MCP-l was incubated in human serum in the presence of 9.6 ⁇ M DP4 Inhibitor Isoleucyl-Thiazolidide (P32/98) for 24 h (C) .
  • the cleavage products were analyzed after 0 min, 10 min, 30 min, Ih, 2h, 3h 5h and 7 h for Glr ⁇ -MCP-l, 0 min, 30 min, Ih, 2h, 3h 5h, 7 h and 24 h for pGlu ⁇ MCP-l and 0 min, Ih, 2h, 3h, 5h, 7 h and 24 h for Gln 1 -MCP-l in combination with Isoleucyl-Thiazolidide using Maldi-TOF mass spectrometry.
  • Figure 19 shows the degradation of human bearing an N-terminal glutaminyl (A) or pyroglutamyl (5-oxo-L-Prolyl) residue (B) by recombinant human DP4 for 24 h.
  • A N-terminal glutaminyl
  • B pyroglutamyl (5-oxo-L-Prolyl) residue
  • MCP-2 was incubated with recombinant human QC for 3 h prior to assay start.
  • the DP4 cleavage products were analyzed using Maldi-TOF mass spectrometry after 0 min, 15 min, 30 min, Ih, 2h, 4h and 24 h.
  • Figure 20 shows the degradation of human MCP-3M-76) carrying an N-terminal glutaminyl (A) or pyroglutamyl (5-oxo-L-Prolyl) residue (B) by recombinant human DP4 for 24 h.
  • A N-terminal glutaminyl
  • B pyroglutamyl (5-oxo-L-Prolyl) residue
  • B pyroglutamyl residue
  • Figure 21 illustrates the cleavage of human MCP-4/]__75 ) bearing an N-terminal glutaminyl (A) or pyroglutamyl (5-oxo-L-Prolyl) residue (B) by recombinant human DP4 for 4 hours.
  • A N-terminal glutaminyl
  • B pyroglutamyl (5-oxo-L-Prolyl) residue
  • Figure 22 shows the chemotactic potency of human N-terminal MCP- 1 variants starting with N-terminal glutamine (Gln 1 -MCP-l) , pyroglutamic acid (pGlu 1 -MCP-l) (5-oxo-L-Proline) , starting with proline 2 (Pro 2 -MCP-l, the aminopeptidase P cleavage product), starting with aspartic acid 3 (Asp 3 -MCP-l, the DP4 cleavage product) and starting with isoleucine 5 (Ile 5 -MCP-l, the MMP-I cleavage product) towards human THP-I monocytes.
  • N-terminal glutamine Gln 1 -MCP-l
  • pGlu 1 -MCP-l pyroglutamic acid
  • pGlu 1 -MCP-l 5-oxo-L-Proline
  • Figure 23 shows the analysis of chemotactic potency of human MCP-I, which was incubated with human recombinant DP4 in presence (Glr ⁇ -MCP-l + QC + DP4) and absence (Glr ⁇ -MCP-l + DP4) of QC-mediated pGlu formation.
  • Figure 24 shows the chemotactic potency of human MCP-I (A) , MCP- 2 (B) , MCP-3 (C) and MCP-4 (D) in absence or presence of the N- terminal pyroglutamyl residue.
  • Figure 25 shows the chemotactic potency of full-length human MCP-I (A), MCP-3 (B), MCP-2 (C) and MCP-4 (D) starting with an N-terminal glutamine in comparison to their respective DP4 cleavage products.
  • Figure 26 shows the significant reduction of TNFCC-levels after application of QC-inhibitor 1- (3- (lH-imidazol-1-yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydrochloride in a model of LPS- induced sepsis in rats (ANOVA, P ⁇ 0.05).
  • Figure 27 shows the dose-dependent reduction of infiltrating monocytes to the peritoneum in a model of thioglycollate-induced peritonitis in mice, caused by a QC-inhibitor .
  • Thioglycollate and QCI (1- (3- (lH-imidazol-1-yl) propyl) -3- (3, 4- dimethoxyphenyl) thiourea hydrochloride) in three different concentrations of 25 mg/kg, 50 mg/kg and 100 mg/kg were injected.
  • Cells infiltrating the peritoneum were classified using FACS analysis 4 h after inducing the peritonits. (*, P ⁇ 0.05, Student's t-test) .
  • Figure 28 shows the reduction of Moma2-positive cells in the peritoneal lavage fluid of mice, which received a thioglycollate challenge in combination with the QC-specific inhibitor QCI (1- (3- (lH-imidazol-1-yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea) , compared to animals receiving no QCI (*, P ⁇ 0.05, Student's t- test) .
  • a QC inhibitor for the treatment and/or prevention of an inflammatory disease or condition selected from a. neurodegenerative diseases, comprising mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, and multiple sclerosis, b. chronic and acute inflammations, comprising rheumatoid arthritis, atherosclerosis, restenosis, and pancreatitis, c. fibrosis, comprising lung fibrosis, liver fibrosis, and renal fibrosis, d. cancer, comprising cancer/hemangioendothelioma proliferation, and gastric carcinomas, e. metabolic diseases, comprising hypertension, f . and other inflammatory diseases, comprising neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis.
  • MCI mild cognitive impairment
  • Alzheimer's disease neurodegeneration in Down Syndrome
  • the QC inhibitor according to item 1 wherein the neurodegenerative disease is selected from mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, multiple sclerosis. 3. The QC inhibitor according to item 1 or 2, wherein the disease is mild cognitive impairment.
  • MCI mild cognitive impairment
  • Alzheimer's disease neurodegeneration in Down Syndrome
  • Familial British Dementia Familial British Dementia
  • Familial Danish Dementia Familial Danish Dementia
  • multiple sclerosis multiple sclerosis.
  • QC inhibitor according to any of items 1 to 3, wherein the QC inhibitor is administered in combination with a further agent, selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • the QC inhibitor according to item 1 wherein the disease is a chronic or acute inflammation, selected from rheumatoid arthritis, atherosclerosis, restenosis and pancreatitis .
  • a further agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-I antagonists and tyrosine kinase inhibitors .
  • ACE angiotensin converting enzyme
  • CB calcium channel blockers
  • beta-blockers beta-blockers
  • platelet aggregation inhibitors cholesterol absorption modulators
  • HMG-Co-A reductase inhibitors high density lipoprotein (HDL) increasing compounds
  • renin inhibitors IL-6 inhibitors
  • a QC inhibitor for the treatment and/or prevention of an inflammatory disease or condition selected from a. neurodegenerative diseases, comprising mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, multiple sclerosis, b. chronic and acute inflammations, comprising rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, c. fibrosis, comprising lung fibrosis, liver fibrosis, renal fibrosis, d. cancer, comprising cancer/hemangioendothelioma proliferation, gastric carcinomas, e. metabolic diseases, comprising hypertension, f . and other inflammatory diseases, comprising neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis.
  • MCI mild cognitive impairment
  • Alzheimer's disease neurodegeneration in Down Syndrome
  • Familial British Dementia Fa
  • the disease is a neurodegenerative disease, selected from mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, multiple sclerosis.
  • MCI mild cognitive impairment
  • Alzheimer's disease neurodegeneration in Down Syndrome
  • Familial British Dementia Familial British Dementia
  • Familial Danish Dementia multiple sclerosis.
  • QC inhibitor is administered in combination with a further agent, selected from the group consisting of nootropic agents, neuroptrotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of nootropic agents, neuroptrotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-I antagonists and tyrosine kinase inhibitors .
  • ACE angiotensin converting enzyme
  • CB calcium channel blockers
  • beta-blockers beta-blockers
  • platelet aggregation inhibitors cholesterol absorption modulators
  • HMG-Co-A reductase inhibitors high density lipoprotein (HDL) increasing compounds
  • renin inhibitors IL-6 inhibitors
  • a QC inhibitor for the preparation of a medicament for treating and/or preventing an inflammatory disease or condition selected from a. neurodegenerative diseases, comprising mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial
  • MCI mild cognitive impairment
  • Alzheimer's disease neurodegeneration in Down Syndrome
  • Familial British Dementia Familial British Dementia
  • Danish Dementia multiple sclerosis, b. chronic and acute inflammations, comprising rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, c. fibrosis, comprising lung fibrosis, liver fibrosis, renal fibrosis, d. cancer, comprising cancer/hemangioendothelioma proliferation, gastric carcinomas, e. metabolic diseases, comprising hypertension, f. and other inflammatory diseases, comprising neuropathic pain, graft rejection/graft failure/graft vasculopathy,
  • the disease is a neurodegenerative disease, selected from mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, multiple sclerosis.
  • MCI mild cognitive impairment
  • Alzheimer's disease neurodegeneration in Down Syndrome
  • Familial British Dementia Familial British Dementia
  • Familial Danish Dementia multiple sclerosis.
  • QC inhibitor is administered in combination with a further agent, selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • the disease is a chronic or acute inflammation, selected from rheumatoid arthritis, atherosclerosis, restenosis and pancreatitis.
  • a further agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE) ; angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-I antagonists and tyrosine kinase inhibitors .
  • ACE angiotensin converting enzyme
  • CFB calcium channel blockers
  • beta-blockers beta-blockers
  • platelet aggregation inhibitors cholesterol absorption modulators
  • HMG-Co-A reductase inhibitors high density lipoprotein (HDL) increasing compounds
  • renin inhibitors IL-6
  • a Method of treatment and/or prevention of an inflammatory disease or condition selected from a. neurodegenerative diseases, comprising mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, multiple sclerosis, b. chronic and acute inflammations, comprising rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, c. fibrosis, comprising lung fibrosis, liver fibrosis, renal fibrosis, d. cancer, comprising cancer / hemangioendothelioma proliferation, gastric carcinomas, e. metabolic diseases, comprising hypertension, f.
  • MCI mild cognitive impairment
  • Alzheimer's disease neurodegeneration in Down Syndrome
  • Familial British Dementia Familial British Dementia
  • Familial Danish Dementia multiple sclerosis
  • chronic and acute inflammations comprising rheumatoid arthritis, atherosclerosis, restenosis,
  • inflammatory diseases comprising neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis, wherein an effective amount of a QC inhibitor is administered to a subject in need thereof.
  • the disease is a neurodegenerative disease, selected from mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, multiple sclerosis .
  • MCI mild cognitive impairment
  • Alzheimer's disease neurodegeneration in Down Syndrome
  • Familial British Dementia Familial British Dementia
  • Familial Danish Dementia Familial Danish Dementia
  • MCI mild cognitive impairment
  • 25 The method of treatment and/or prevention according to any of items 23 to 25, wherein the QC inhibitor is administered in combination with a further agent, selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-I antagonists and tyrosine kinase inhibitors.
  • ACE angiotensin converting enzyme
  • CB calcium channel blockers
  • beta-blockers beta-blockers
  • platelet aggregation inhibitors cholesterol absorption modulators
  • HMG-Co-A reductase inhibitors high density lipoprotein (HDL) increasing compounds
  • renin inhibitors IL-6 inhibitors
  • QC inhibitor is an inhibitor selected from formulae 1, 1*, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and Ii.
  • Diagnostic assay comprising a QC inhibitor.
  • a method of diagnosing any one of the diseases and/or conditions as defined in item 1, comprising the steps of collecting a sample from a subject who is suspected to be afflicted with said disease and/or condition, contacting said sample with a QC inhibitor, and determining whether or not said subject is afflicted by said disease and/or condition.
  • Diagnostic kit for carrying out the method of items 38 to 42 comprising as detection means the diagnostic assay of any of items 34 or 37 and a determination means.
  • composition comprising the QC inhibitor according to any of items 1 to 7 or 31 to 33.
  • the invention relates to the use of a QC inhibitor in methods of treating a chronic or acute inflammation, selected from rheumatoid arthritis, atherosclerosis, restenosis and pancreatitis, particularly restenosis and pancreatitis, most preferably restenosis.
  • a QC inhibitor for treating a chronic or acute inflammation selected from rheumatoid arthritis, atherosclerosis, restenosis and pancreatitis, can be tested using the in vivo assays described in examples 3, 7 and 8 of the present invention.
  • MCI mild cognitive impairment
  • a QC inhibitor for the treatment and/or prevention of an inflammatory disease or condition selected from mild cognitive impairment (MCI), restenosis, and pancreatitis.
  • a QC inhibitor for the treatment and/or prevention of an inflammatory disease or condition selected from mild cognitive impairment (MCI), restenosis, and pancreatitis.
  • MCI mild cognitive impairment
  • restenosis restenosis
  • pancreatitis pancreatitis
  • a QC inhibitor for the preparation of a medicament for treating and/or preventing an inflammatory disease or condition selected from mild cognitive impairment (MCI), restenosis, and pancreatitis.
  • MCI mild cognitive impairment
  • restenosis restenosis
  • pancreatitis an inflammatory disease or condition selected from mild cognitive impairment (MCI), restenosis, and pancreatitis.
  • QC inhibitor or use according to any of items 1 to 4, wherein the QC inhibitor is administered in combination with a further agent, selected from the group consisting of nootropic agents, neuroptrotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of nootropic agents, neuroptrotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-I antagonists and tyrosine kinase inhibitors.
  • ACE angiotensin converting enzyme
  • CB calcium channel blockers
  • beta-blockers beta-blockers
  • platelet aggregation inhibitors cholesterol absorption modulators
  • HMG-Co-A reductase inhibitors high density lipoprotein (HDL) increasing compounds
  • renin inhibitors IL-6 inhibitors
  • a Method of treatment and/or prevention of an inflammatory disease or condition selected from mild cognitive impairment (MCI), restenosis and pancreatitis, wherein an effective amount of a QC inhibitor is administered to a subject in need thereof.
  • MCI mild cognitive impairment
  • QC inhibitor an effective amount of a QC inhibitor is administered to a subject in need thereof.
  • a further agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • a further agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors;
  • ACE angiotensin converting enzyme
  • CCB calcium channel blockers
  • beta-blockers beta-blockers
  • platelet aggregation inhibitors cholesterol absorption modulators
  • HMG-Co-A reductase inhibitors HMG-Co-A reductase inhibitors
  • HDL high density lipoprotein
  • IL-6 inhibitors antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-I antagonists and tyrosine kinase inhibitors.
  • Diagnostic assay comprising a QC inhibitor.
  • a method of diagnosing any one of the diseases and/or conditions as defined in item 1, comprising the steps of collecting a sample from a subject who is suspected to be afflicted with said disease and/or condition, contacting said sample with an inhibitor of a glutaminyl peptide cyclotransferase, and determining whether or not said subject is afflicted by said disease and/or condition.
  • QC inhibitor is 1- (3- (lH-imidazole-1-yl) propyl) -3- (3, 4- dimethoxy-phenyl) thiourea hydrochloride.
  • Diagnostic kit for carrying out the method of items 25 to 30 comprising as detection means the diagnostic assay of any of items 21 to 24 and a determination means.
  • composition comprising the QC inhibitor according to any of items 1, 4 to 6 or 18 to 20.
  • Enzyme inhibitors in particular inhibitors of QC
  • Reversible enzyme inhibitors comprise competitive inhibitors, non-competitive reversible inhibitors, slow-binding or tight- binding inhibitors, transition state analogues and multisubstrate analogues.
  • Slow-binding or tight-binding inhibitors i) are competitive inhibitors where the equilibrium between inhibitor and enzyme is reached slowly, ii) (k on is slow) , possibly due to conformational changes that must occur in the enzyme or inhibitor a) are often transition state analogues b) are effective at concentrations similar to the enzyme concentration (subnanomolar KD values) c) due to k off values being so low these types of inhibitors are "almost" irreversible.
  • Multisubstrate analogues For a reaction involving two or more substrates, a competitive inhibitor or transition state analogue can be designed which contains structural characteristics resembling two or more of the substrates.
  • Irreversible enzyme inhibitors drive the equilibrium between the unbound enzyme and inhibitor and enzyme inhibitor complex (E
  • Active-site directed irreversible inhibitors are recognized by the enzyme (reversible, specific binding) followed by covalent bond formation, and i) are structurally similar to substrate, transition state or product allowing for specific interaction between drug and target enzyme, ii) contain reactive functional group (e.g. a nucleophile, -COCH2Br) allowing for covalent bond formation.
  • reactive functional group e.g. a nucleophile, -COCH2Br
  • reaction scheme describes an active-site directed reagent with its target enzyme where K is the dissociation constant and kmactivation is the rate of covalent bond formation.
  • Mechanism-based enzyme inactivators are active-site directed reagents (unreactive) which bind to the enzyme active site where they are transformed to a reactive form (activated) by the enzyme's catalytic capabilities. Once activated, a covalent bond between the inhibitor and the enzyme is formed.
  • the reaction scheme below shows the mechanism of action of a mechanism based enzyme inactivator, where K D is the dissociation complex, k2 is the rate of activation of the inhibitor once bound to the enzyme, k3 is the rate of dissociation of the activated inhibitor, P, from the enzyme (product can still be reactive) from the enzyme and k ⁇ is the rate of covalent bond formation between the activated inhibitor and the enzyme.
  • Inactivation covalent bond formation, ⁇ kq
  • dissociation k3
  • the partition ratio, k ⁇ /kq: ratio of released product to inactivation should be minimized for efficient inactivation of the system and minimal undesirable side reactions.
  • Uncompetitive enzyme inhibitors As a definition of uncompetitive inhibitor (an inhibitor which binds only to ES complexes) the following equilibria equation can be assumed:
  • the ES complex dissociates the subtrate with a dissociation constant equal to Ks, whereas the ESI complex does not dissociate it (i.e has a Ks value equal to zero) .
  • the Km's of Michaelis-Menten type enzymes are expected to be reduced.
  • Increasing substrate concentration leads to increasing ESI concentration (a complex incapable of progressing to reaction products) therefore the inhibition cannot be removed.
  • Preferred according to the present invention are competitive enzyme inhibitors.
  • K or "K” and “K” are binding constants, which describe the binding of an inhibitor to and the subsequent release from an enzyme. Another measure is the “IC50” value, which reflects the inhibitor concentration, which at a given substrate concentration results in 50 % enzyme activity.
  • QC as used herein comprises glutaminyl cyclase (QC) and QC-like enzymes.
  • QC and QC-like enzymes have identical or similar enzymatic activity, further defined as QC activity.
  • QC-like enzymes can fundamentally differ in their molecular structure from QC.
  • QC activity is defined as intramolecular cyclization of N-terminal glutaminyl residues into pyroglutamic acid (pGlu*) or of N-terminal L-homoglutaminyl or L-beta-homoglutaminyl to a cyclic pyro-homoglutamine derivative under liberation of ammonia. See schemes 1 and 2 in this regard.
  • EC as used herein comprises the side activity of QC and QC-like enzymes as glutamate cyclase (EC) , further defined as EC activity.
  • EC activity is defined as intramolecular cyclization of N-terminal glutamyl residues into pyroglutamic acid (pGlu*) by QC. See scheme 3 in this regard. Scheme 3: N-terminal cyclization of uncharged glutamyl peptides by QC (EC)
  • QC-inhibitor "glutaminyl cyclase inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors as generally defined above, which inhibit the catalytic activity of glutaminyl cyclase (QC) or its glutamyl cyclase (EC) activity.
  • the subject method and medical use utilize an agent with a K 1 for QC inhibition of 10 ⁇ M or less, more preferably of 1 ⁇ M or less, even more preferably of 0.1 ⁇ M or less or 0.01 ⁇ M or less, or most preferably 0.001 ⁇ M or less.
  • K 1 for QC inhibition 10 ⁇ M or less, more preferably of 1 ⁇ M or less, even more preferably of 0.1 ⁇ M or less or 0.01 ⁇ M or less, or most preferably 0.001 ⁇ M or less.
  • K 1 for QC inhibition of 10 ⁇ M or less, more preferably of 1 ⁇ M or less, even more preferably of 0.1 ⁇ M or less or 0.01 ⁇ M or less, or most preferably 0.001 ⁇ M or less.
  • the QC inhibitors of the subject method or medical use will be small molecules, e.g., with molecular weights of 1000 g/mole or less, 500 g/mole or less, preferably of 400 g/mole or less, and even more preferably of 350 g/mole or less and even of 300 g/mole or less.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment and/or is suspected of being afflicted with a disease and/or condition as defined in the items.
  • terapéuticaally effective amount means that amount of an active compound or a pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the term "pharmaceutically acceptable” embraces both human and veterinary use: for example the term “pharmaceutically acceptable” embraces a veterinary acceptable compound or a compound acceptable in human medicine and health care .
  • Salts and solvates of the inhibitors of the present invention and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts and solvates.
  • Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalene-disulphonic) , salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl,
  • compositions for example 1, 4-benzenediacrylic
  • isethionic acids perchloric, propionic, glycolic, hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic, saccharinic and trifluoroacetic acid.
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D-glutamine .
  • solvates include hydrates.
  • crystalline forms of the inhibitors may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the inhibitors, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the present invention further includes within its scope prodrugs of the inhibitors of this invention.
  • prodrugs will be functional derivatives of the inhibitors, which are readily convertible in vivo into the desired therapeutically active inhibitors.
  • the term "administering" shall encompass the treatment of the various disorders described with prodrug versions of one or more of the itemed inhibitors, but which converts to the above specified inhibitors in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985 and the patent applications DE 198 28 113, DE 198 28 114, WO 99/67228 and WO 99/67279 which are fully incorporated herein by reference.
  • any of the processes for preparation of the inhibitors of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, fully incorporated herein by reference.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • composition is intended to encompass a product comprising the itemed compounds in the therapeutically effective amounts, as well as any product, which results, directly or indirectly, from combinations of the itemed compounds .
  • suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Carriers which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, disintegrating agents, dyes and colouring agents.
  • Soluble polymers as targetable drug carriers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmeth- acrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolyllysine substituted with palmitoyl residue (s).
  • the inhibitors of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled/sustained release of a drug, for example, poly actic acid, poly-epsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrating agents include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • QC-inhibitors which are suitable for uses and methods according to the present invention are disclosed in WO 2005/075436, which is incorporated herein in its entirety with regard to the structure, synthesis and methods of use of the QC-inhibitors.
  • the present invention provides novel inhibitors of QC (EC) of the formula 1,
  • A is either: an alkyl chain, alkenyl chain or alkynyl chain; or A is a group selected from:
  • R 6 , R 7 , R 8 , R 9 and R 10 are independently H or an alkyl chain, alkenyl chain, alkynyl chain, cycloalkyl, a carbocycle, aryl, heteroaryl, or a heterocycle; n and n 1 are independently 1 - 5; m is 1 - 5 ; o is 0 - 4;
  • D and E independently represent an alkyl chain, alkenyl chain, alkynyl chain, a cycloalkyl, carbocycle, aryl, -alkylaryl, heteroaryl, -alkylheteroaryl, acyl or a heterocycle.
  • R 19 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, -oxyalkyl, -oxyaryl, carbonyl, amido, hydroxy, NO2, NH 2 , CN;
  • R and R are independently selected from H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, , -oxyalkyl, oxyaryl, carbonyl, amido, NO 2 , NH 2 , CN, CF 3 ;
  • X 1 , X 2 and X 3 are independently O or S provided that X 2 and X 3 are not both O;
  • Y is 0 or S, with the proviso that Y may not be 0, when the carbocycle formed by R 17 and R 18 has 3 members in the ring;
  • Z is CH or N
  • R 11 , R 12 , R 13 and R 14 can be independently selected from H, an alkyl chain, an alkenyl chain, an alkynyl chain, cycloalkyl, carbocycle, aryl, heteroaryl, a heterocycle, halogen, alkoxy-, -thioalkyl, carboxyl, carboxylic acid ester, carbonyl, carbamide, carbimide, thiocarbamide or thiocarbonyl, NH 2 , NO 2 ;
  • R 15 and R 16 are independently of each other H or a branched or unbranched alkyl chain, or a branched or unbranched alkenyl chain;
  • R 17 and R 18 are independently selected from H or an alkyl chain, alkenyl chain, a alkynyl chain, a carbocycle, aryl, heteroaryl, heteroalkyl or can be connected to form a carbocycle with up to 6 ring atoms;
  • n 0 or 1
  • A is selected from an alkyl chain, alkenyl chain or alkynyl chain
  • A is a C1-C7 alkyl chain, C1-C7 alkenyl chain or a C1-C7 alkynyl chain.
  • A is an unbranched C2-5 alkyl chain, in particular an unbranched C3-4 alkyl chain, especially an unbranched C 3 alkyl chain.
  • A represents a C3 alkyl chain which is substituted at the 2 position by one (i.e. in S or R configuration) or two methyl groups.
  • A represents a group of formula (I), (II) or (III), wherein n and n 1 are each equal to 1 and R 6 , R 7 , R 8 , R 9 and R 10 represent H.
  • R 6 , R 7 , R 8 , R 9 and R 10 represent H or methyl.
  • the group B is chosen from (VI), (Via), (VIb), (VII), (X), (XI), (XII), (XIII) and (XIV).
  • group B represents formula (VI) .
  • formula (VIa) In a third embodiment of the invention group B represents formula (Via) .
  • formula (VIb) In a fourth embodiment of the invention group B represents formula (VIb) .
  • formula (VII) In a sixth embodiment of the invention group B represents formula (X) .
  • a seventh embodiment of the invention group B represents formula (XI) .
  • In an eighth embodiment of the invention group B represents formula (XII).
  • another embodiment of the invention group B represents formula (XIII) .
  • formula (XIV) In a preferred embodiment of the invention B represents a group of formula (VI) or (VII) .
  • B represents a group (IX) suitably A does not represent alkynyl .
  • D and E independently represent benzyl, aryl, heteroaryl or a heterocycle.
  • D and E represent aryl, in particular phenyl or napthyl, especially substituted phenyl.
  • Preferred substituent groups when D represents phenyl include alkoxy-, -thioalkyl, halogen, or a carboxylic acid alkyl or aryl ester. Also preferred are fluoro, chloro, bromo, iodo, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, benzyloxy, cyano, acetyl, dimethyl amino, methylsulphanyl, nitro, oxazolyl, pyrazolyl, isopropyl, ethyl and methoxycarbonyl . Where a phenyl group is mono-substituted it is preferred that substitution is in the 4-position.
  • Suitable aryl groups which D and E may represent include dihydrobenzodioxine, benzodioxole, benzodithiole dihydrobenzodithiine, benzooxathiole and dihydrobenzooxathiine .
  • a particularly preferred group, which D or E may represent is 3, 4- (dimethoxy) -phenyl,
  • R 20 and R 21 represent NO 2 , CN, CF 3 or, if R 20 is H, R 21 is NO 2 , CN, CF 3 , or, if R 21 is H, R 20 is NO 2 , CN, CF 3 .
  • X or Y is S, 0 or NR 1 .
  • X or Y is S.
  • Z represents N.
  • R 11 and R 14 are H.
  • R 12 and R 13 are independently selected from oxyalkyl or thioalkyl, halogen, or carboxylic acid alkyl ester or phenyl.
  • At least one of R 15 and R 16 is H, more preferably, R 15 and R 16 are both H.
  • one of R 17 and R 18 is H and the other iiss MMee.
  • compounds wwhheerree RR 1177 aaind R 18 form a carbocycle with up to 6 members in the ring atoms .
  • Preferred compounds include those defined by Examples 13, 119 and 125 below.
  • the present invention provides compounds of formula 1 for use as a pharmaceutical.
  • the compounds of formula 1 in one embodiment regarding the use of the compounds of formula 1 as a pharmaceutical, the compounds:
  • the compound (a) of the proviso above is disclosed as compound 7 in Ganellin et al (1995) J Med Chem 38(17) 3342-3350. This paper discloses said compound as a weak inhibitor of the histamine H3 receptor.
  • the compound of proviso (b) is disclosed as compound 7 in Venkatachalam et al (2001) Bioorganic Med Chem Lett 11, 523-528. This discloses said compound as an HIVl reverse transcriptase inhibitor .
  • the compound of proviso (c) is disclosed as compound 19b in Moon et al (1991) J Med Chem 34, 2314-2327. This paper discloses said compound as a cholinergic agonist with potential use in the treatment of Alzheimer's disease.
  • proviso (d) The compounds of proviso (d) are disclosed as compounds 99, 100 and 102-103 in Wright et al (1986) J Med Chem 29, 523-530. This paper discloses said compounds as thromoxane synthetase inhibitors .
  • inhibitors of QC are those of formula Ia,
  • R is defined in examples 1 to 53.
  • inhibitors of QC are those of formula Ib, wherein R 1 and R 2 are defined in examples 54 to 95.
  • inhibitors of QC are those of formula Ic, wherein R 3 is defined in examples 96 to 102.
  • R and R are defined in examples 106 to 109,
  • inhibitors of QC are those of formula Ig, wherein R 7 , R 8 and R 9 are defined in examples 113 to 132.
  • inhibitors of QC are those of formula Ih, wherein n is defined in examples 133 to 135.
  • inhibitors of QC are those of formula Ii, wherein m is defined in examples 136 and 137.
  • inhibitors of QC are those of formula 13 ⁇ to 141.
  • a preferred inhibitor of glutaminyl peptide cyclotransferase is 1- (3- (lH-imidazol-1-yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydrochloride (further named as QCI)
  • the present invention provides a composition, preferably a pharmaceutical composition, comprising at least one QC inhibitor optionally in combination with at least one other agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • at least one QC inhibitor optionally in combination with at least one other agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • the aforementioned other agent is selected from the group consisting of beta-amyloid antibodies, cysteine protease inhibitors, PEP-inhibitors, LiCl, acetylcholinesterase
  • AFOE PIMT enhancers
  • inhibitors of beta secretases inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE- 4), TNFalpha inhibitors, muscarinic Ml receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents, MCP-I antagonists or an agent selected from the group consisting of antegren (natalizumab) , Neurelan (fampridine-SR) , campath (alemtuzumab) , IR 208, NBI 5788/MSP 771 (tiplimotide) , paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene) , BAY 361677 (interleukin-4) , matrix- metalloproteinase-inhibitors
  • the other agent may be, for example, an antianxiety drug or antidepressant selected from the group consisting of
  • Benzodiazepines e.g. alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, fludiazepam, loflazepate, lorazepam, methaqualone, oxazepam, prazepam, tranxene,
  • alprazolam chlordiazepoxide
  • clobazam clonazepam
  • clorazepate diazepam
  • fludiazepam fludiazepam
  • loflazepate lorazepam
  • methaqualone oxazepam
  • prazepam tranxene
  • SSRI' s Selective serotonin re-uptake inhibitors
  • SSRI' s Selective serotonin re-uptake inhibitors
  • Tricyclic antidepressants e.g. amitryptiline, clomipramine, desipramine, doxepin, imipramine
  • Azapirones e.g. buspirone, tandopsirone
  • Serotonin-norepinephrine reuptake inhibitors e.g. venlafaxine, duloxetine
  • NRI' s Norepinephrine reuptake inhibitors
  • reboxetine e.g. reboxetine
  • Bupropione e.g. Bupropione
  • Nefazodone e.g. Nefazodone
  • NPY-receptor ligands NPY agonists or antagonists.
  • the other agent may be, for example, an anti-multiple sclerosis drug selected from the group consisting of a) dihydroorotate dehydrogenase inhibitors, e.g. SC-12267, teriflunomide, MNA-715, HMR-1279 (syn. to HMR-1715, MNA- 279), b) autoimmune suppressant, e.g. laquinimod, c) paclitaxel, d) antibodies, e.g.
  • an anti-multiple sclerosis drug selected from the group consisting of a) dihydroorotate dehydrogenase inhibitors, e.g. SC-12267, teriflunomide, MNA-715, HMR-1279 (syn. to HMR-1715, MNA- 279), b) autoimmune suppressant, e.g. laquinimod, c) paclitaxel, d) antibodies, e.g.
  • AGT-I anti-granulocyte-macrophage colony- stimulating factor (GM-CSF) monoclonal antibody, Nogo receptor modulators, ABT-874, alemtuzumab (CAMPATH), anti- OX40 antibody, CNTO-1275, DN-1921, natalizumab (syn. to AN- 100226, Antegren, VLA-4 Mab) , daclizumab (syn. to Zenepax, Ro-34-7375, SMART anti-Tac) , J-695, priliximab (syn.
  • GM-CSF granulocyte-macrophage colony- stimulating factor
  • peptide nucleic acid (PNA) preparations e.g. reticulose
  • interferon alpha e.g. Alfaferone, human alpha interferon
  • interferon beta e.g. Frone, interferon beta-la like Avonex, Betron (Rebif) , interferon beta analogs, interferon beta-transferrin fusion protein, recombinant interferon beta-lb like Betaseron, h) interferon tau, i) peptides, e.g. AT-008, AnergiX.MS, Immunokine (alpha-
  • Immunokine-NNS03 cyclic peptides like ZD-7349, j) therapeutic enzymes, e.g. soluble CD8 (sCD8), k) multiple sclerosis-specific autoantigen-encoding plasmid and cytokine-encoding plasmid, e.g. BHT-3009;
  • TNF-alpha e.g. BLX-1002, thalidomide, SH-636, m
  • TNF antagonists e.g. solimastat, lenercept (syn. to RO-45-
  • TNF alpha e.g. etanercept (syn. to Enbrel, TNR-OOl)
  • CD28 antagonists e.g. abatacept
  • p) Lck tyrosine kinase inhibitors q) cathepsin K inhibitors
  • analogs of the neuron-targeting membrane transporter protein taurine and the plant-derived calpain inhibitor leupeptin e.g. Neurodur
  • chemokine receptor-1 (CCRl) antagonist e.g. BX-471, t) CCR2 antagonists
  • AMPA receptor antagonists e.g. ER-167288-01 and ER-099487
  • L-alanine e.g. glatiramer acetate (syn. to Copaxone, COP- 1, copolymer-1) , dd) topoisomerase II modulators, e.g. mitoxantrone hydrochloride, ee) adenosine deaminase inhibitor, e.g. cladribine (syn. to
  • interleukin-10 e.g. ilodecakin (syn. to Tenovil, Sch-
  • interleukin-12 antagonists e.g. lisofylline (syn. to
  • TGF-beta e.g. GDF-I (growth and differentiation factor
  • TGF-beta-2 e.g. BetaKine, mm
  • MMP inhibitors e.g. glycomed, nn) phosphodiesterase 4 (PDE4) inhibitors, e.g. RPR-122818, oo) purine nucleoside phosphorylase inhibitors, e.g. 9- (3- pyridylmethyl) -9-deazaguanine, peldesine (syn. to BCX-34, TO-200) , pp) alpha-4/beta-l integrin antagonists, e.g. ISIS-104278, qq) antisense alpha4 integrin (CD49d), e.g. ISIS-17044,
  • MCP-I inhibitors e.g. nucleosides, ICN-17261, ss) cytokine inhibitor
  • compositions e.g. for parenteral, enteral or oral administration, comprising at least one QC inhibitor, optionally in combination with at least one of the other aforementioned agents .
  • the invention provides a method for the treatment of these conditions .
  • the method comprises either co-administration of at least one QC inhibitor and at least one of the other agents or the sequential administration thereof.
  • Co-administration includes administration of a formulation, which comprises at least one QC inhibitor and at least one of the other agents or the essentially simultaneous administration of separate formulations of each agent.
  • Beta-amyloid antibodies and compositions containing the same are described, e.g. in WO 2006/137354, WO 2006/118959, WO
  • beta-amyloid antibodies may be selected from, for example, polyclonal, monoclonal, chimenic or humanited antibodies. Furthermore, said antibodies may be useful to develop active and passive immune therapies, i.e. vaccines and monoclonal antibodies.
  • beta-amyloid antibodies are ACU-5A5, huC091 (Acumen/Merck); PF-4360365, RI-1014, RI-1219, RI-409, RN-1219 (Rinat Neuroscience Corp (Pfizer Inc) ) ; the nanobody therapeutics of Ablynx/Boehringer Ingelheim; beta-amyloid- specific humanized monoclonal antibodies of Intellect
  • a suitable antibody, which recognize the A ⁇ -N-Terminus is, for example Acl-24 (AC immune CA) .
  • a monoclonal antibody against beta-amyloid peptide is disclosed in WO 2007/068412.
  • Respective chimenic and humanized antibodies are disclosed in WO 2008/011348.
  • a method for producing a vaccine composition for treating an amyloid-associated diease si disclosed in WO 2007/068411.
  • Suitable cysteine protease inhibitors are for example inhibitors of cathepsin B.
  • Inhibitors of cathepsin B and compositions containing such inhibitors are described, e.g. in WO 2006/060473, WO 2006/042103, WO 2006/039807, WO 2006/021413, WO 2006/021409, WO 2005/097103, WO 2005/007199, WO2004/084830, WO 2004/078908, WO 2004/026851, WO 2002/094881, WO 2002/027418, WO 2002/021509, WO 1998/046559, WO 1996/021655.
  • PIMT enhancers are 10-aminoaliphatyl- dibenz[b, f] oxepines described in WO 98/15647 and WO 03/057204, respectively. Further useful according to the present invention are modulators of PIMT activity described in WO 2004/039773.
  • Inhibitors of beta secretase and compositions containing such inhibitors are described, e.g. in WO 03/059346, WO 2006/099352, WO 2006/078576, WO 2006/060109, WO 2006/057983, WO 2006/057945, WO 2006/055434, WO 2006/044497, WO 2006/034296, WO 2006/034277, WO 2006/029850, WO 2006/026204, WO 2006/014944, WO 2006/014762, WO 2006/002004, US 7,109,217, WO 2005/113484, WO 2005/103043, WO 2005/103020, WO 2005/065195, WO 2005/051914, WO 2005/044830, WO 2005/032471, WO 2005/018545, WO 2005/004803, WO 2005/004802, WO 2004/062625, WO 2004/043916, WO 2004/013098, WO 03/099202,
  • beta secretase inhibitors for the purpose of the present invention are WY-25105 (Wyeth) ; Posiphen, (+) - phenserine (TorreyPines / NIH); LSN-2434074, LY-2070275, LY- 2070273, LY-2070102 (Eli Lilly & Co.); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312, PNU-38773, PNU-90530 (Elan / Pfizer);
  • Inhibitors of gamma secretase and compositions containing such inhibitors are described, e.g. in WO 2005/008250, WO 2006/004880, US 7,122,675, US 7,030,239, US 6,992,081, US 6,982,264, WO 2005/097768, WO2005/028440, WO 2004/101562, US 6,756,511, US 6,683,091, WO 03/066592, WO 03/014075, WO 03/013527, WO 02/36555, WO 01/53255, US 7,109,217, US 7,101,895, US 7,049,296, US 7,034,182, US 6,984,626, WO 2005/040126, WO 2005/030731, WO 2005/014553, US 6,890,956, EP 1334085, EP 1263774, WO 2004/101538, WO 2004/00958, WO 2004/089911, WO 2004/073630, WO 2004/069826,
  • Suitable gamma secretase inhibitors for the purpose of the present invention are GSI-953, WAY-GSI-A, WAY-GSI-B (Wyeth) ; MK- 0752, MRK-560, L-852505, L-685-458, L-852631, L-852646 (Merck & Co. Inc.); LY-450139, LY-411575, AN-37124 (Eli Lilly & Co.); BMS-299897, BMS-433796 (Bristol-Myers Squibb Co.); E-2012 (Eisai Co. Ltd.); EHT-0206, EHT-206 (ExonHit Therapeutics SA); and NGX-555 (TorreyPines Therapeutics Inc.).
  • Suitable beta amyloid synthesis inhibitors for the purpose of the present invention are for example Bisnorcymserine (Axonyx Inc.); (R) -flurbiprofen (MCP-7869; Flurizan) (Myriad Genetics); nitroflurbiprofen (NicOx) ; BGC-20-0406 (Sankyo Co. Ltd.) and BGC-20-0466 (BTG pIc).
  • Suitable amyloid protein deposition inhibitors for the purpose of the present invention are for example SP-233 (Samaritan
  • AZD-103 Ellipsis Neurotherapeutics Inc.
  • AAB-OOl (Bapineuzumab) , AAB-002, ACC-OOl (Elan Corp pic);
  • AdPEDI- (amyloid-betal-6) 11) (Vaxin Inc.); MPI-127585, MPI-423948 (Mayo Foundation) ; SP-08 (Georgetown University) ; ACU-5A5
  • Suitable PDE-4 inhibitors for the purpose of the present invention are for example Doxofylline (Instituto Biologico Chemioterapica ABC SpA.); idudilast eye drops, tipelukast, ibudilast (Kyorin Pharmaceutical Co.
  • MAO inhibitors and compositions containing such inhibitors are described, e.g. in WO 2006/091988, WO 2005/007614, WO 2004/089351, WO 01/26656, WO 01/12176, WO 99/57120, WO 99/57119, WO 99/13878, WO 98/40102, WO 98/01157, WO 96/20946, WO 94/07890 and WO 92/21333.
  • Suitable MAO-inhibitors for the purpose of the present invention are for example Linezolid (Pharmacia Corp.); RWJ-416457 (RW Johnson Pharmaceutical Research Institute) ; budipine (Altana AG); GPX-325 (BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine; indantadol (Chiesi Farmaceutici SpA.); moclobemide (Roche Holding AG); SL-25.1131 (Sanofi-Synthelabo) ;
  • Suitable histamine H3 antagonists for the purpose of the present invention are, e.g. ABT-239, ABT-834 (Abbott Laboratories);
  • PEP inhibitors and compositions containing such inhibitors are described, e.g. in JP 01042465, JP 03031298, JP 04208299, WO 00/71144, US 5,847,155; JP 09040693, JP 10077300, JP 05331072, JP 05015314, WO 95/15310, WO 93/00361, EP 0556482, JP 06234693, JP 01068396, EP 0709373, US 5,965,556, US 5,756,763, US 6,121,311, JP 63264454, JP 64000069, JP 63162672, EP 0268190, EP 0277588, EP 0275482, US 4,977,180, US 5,091,406, US 4,983,624, US 5,112,847, US 5,100,904, US 5,254,550, US 5,262,431, US 5,340,832, US 4,956,380, EP 0303434, JP 03056486, JP 01143897, JP
  • Suitable prolyl endopeptidase inhibitors for the purpose of the present invention are, e.g. Fmoc-Ala-Pyrr-CN, Z-Phe-Pro- Benzothiazole (Probiodrug) , Z-321 (Zeria Pharmaceutical Co Ltd.); ONO-1603 (Ono Pharmaceutical Co Ltd); JTP-4819 (Japan Tobacco Inc.) and S-17092 (Servier) .
  • NPY neuropeptide Y
  • NPY mimetic NPY mimetic
  • NPY agonist or antagonist NPY agonist or antagonist
  • ligand of the NPY receptors NPY receptors
  • Preferred according to the present invention are antagonists of the NPY receptors.
  • Suitable ligands or antagonists of the NPY receptors are 3a, 4 , 5, 9b-tetrahydro-lh-benz [e] indol-2-yl amine-derived compounds as disclosed in WO 00/68197.
  • NPY receptor antagonists which may be mentioned include those disclosed in European patent applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; WO 00/30674, US patents Nos.
  • NPY antagonists include those compounds that are specifically disclosed in these patent documents. More preferred compounds include amino acid and non-peptide-based NPY antagonists.
  • Amino acid and non-peptide-based NPY antagonists which may be mentioned include those disclosed in European patent applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498 ; US patents Nos. 5,552,411, 5,663,192 and 5,5
  • Particularly preferred compounds include amino acid-based NPY antagonists.
  • Amino acid-based compounds which may be mentioned include those disclosed in international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 97/19914 or, preferably, WO 99/15498.
  • Preferred amino acid-based NPY antagonists include those that are specifically disclosed in these patent documents, for example BIBP3226 and, especially, (R) -N2- (diphenylacetyl) - (R) -N- [ 1- (4-hydroxy- phenyl) ethyl] arginine amide (Example 4 of international patent application WO 99/15498) .
  • Ml receptor agonists and compositions containing such inhibitors are described, e.g. in WO 2004/087158, WO 91/10664.
  • Suitable Ml receptor antagonists for the purpose of the present invention are for example CDD-0102 (Cognitive Pharmaceuticals) ; Cevimeline (Evoxac) (Snow Brand Milk Products Co.
  • Acetylcholinesterase inhibitors and compositions containing such inhibitors are described, e.g. in WO 2006/071274, WO 2006/070394, WO 2006/040688, WO 2005/092009, WO 2005/079789, WO 2005/039580, WO 2005/027975, WO 2004/084884, WO 2004/037234, WO 2004/032929, WO 03/101458, WO 03/091220, WO 03/082820, WO 03/020289, WO 02/32412, WO 01/85145, WO 01/78728, WO 01/66096, WO 00/02549, WO 01/00215, WO 00/15205, WO 00/23057, WO 00/33840, WO 00/30446, WO 00/23057, WO 00/15205, WO 00/09483, WO 00/07600, WO 00/02549, WO 99/
  • Suitable acetylcholinesterase inhibitors for the purpose of the present invention are for example Donepezil (Eisai Co. Ltd.); rivastigmine (Novartis AG); (-) -phenserine (TorreyPines Therapeutics) ; ladostigil (Hebrew University of Jerusalem) ; huperzine A (Mayo Foundation) ; galantamine (Johnson & Johnson) ;
  • BGC-20-1259 (Sankyo Co. Ltd.); physostigmine (Forest Laboratories Inc.); NP-0361 (Neuropharma SA); ZT-I (Debiopharm) ; tacrine (Warner-Lambert Co.); metrifonate (Bayer Corp.) and INM-176 (Whanln) .
  • NMDA receptor antagonists and compositions containing such inhibitors are described, e.g. in WO 2006/094674, WO 2006/058236, WO 2006/058059, WO 2006/010965, WO 2005/000216, WO 2005/102390, WO 2005/079779, WO 2005/079756, WO 2005/072705, WO 2005/070429, WO 2005/055996, WO 2005/035522, WO 2005/009421, WO 2005/000216, WO 2004/092189, WO 2004/039371, WO 2004/028522, WO 2004/009062, WO 03/010159, WO 02/072542, WO 02/34718, WO 01/98262, WO 01/94321, WO 01/92204, WO 01/81295, WO 01/32640, WO 01/10833, WO 01/10831, WO 00/56711, WO 00/29023, WO
  • Suitable NMDA receptor antagonists for the purpose of the present invention are for example Memantine (Merz & Co. GmbH); topiramate (Johnson & Johnson) ; AVP-923 (Neurodex) (Center for Neurologic Study); EN-3231 (Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579) (Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals Inc.); dexanabinol (HU-211; Sinnabidol; PA- 50211) (Pharmos) ; EpiCept NP-I (Dalhousie University); indantadol (V-3381; CNP-3381) (Vernalis) ; perzinfotel (EAA-090, WAY-126090, EAA-129) (Wyeth) ; RGH-896 (Gedeon Richter Ltd.); traxoprodil (CP-101606), besonprodil (PD-196860, CI-1041) (
  • the present invention relates to combination therapies useful for the treatment of atherosclerosis, restenosis, pancreatitis or arthritis, administering a QC inhibitor in combination with another therapeutic agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-I antagonists and tyrosine kinase inhibitors providing beneficial or synergistic therapeutic effects over each monotherapy component alone.
  • ACE angiotensin converting enzyme
  • CB calcium channel blockers
  • beta-blockers beta-blockers
  • Angiotensin II receptor blockers are understood to be those active agents that bind to the ATI -receptor subtype of angiotensin II receptor but do not result in activation of the receptor. As a consequence of the blockade of the ATI receptor, these antagonists can, e.g. be employed as antihypertensive agents .
  • Suitable angiotensin II receptor blockers which may be employed in the combination of the present invention include ATi receptor antagonists having differing structural features, preferred are those with non-peptidic structures.
  • ATi receptor antagonists having differing structural features, preferred are those with non-peptidic structures.
  • Preferred ATI-receptor antagonists are those agents that have been approved and reached the market, most preferred is valsartan, or a pharmaceutically acceptable salt thereof.
  • the interruption of the enzymatic degradation of angiotensin to angiotensin II with ACE inhibitors is a successful variant for the regulation of blood pressure and thus also makes available a therapeutic method for the treatment of hypertension.
  • a suitable ACE inhibitor to be employed in the combination of the present invention is, e.g. a compound selected from the group consisting alacepril, benazepril, benazeprilat ; captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril and trandolapril, or in each case, a pharmaceutically acceptable salt thereof.
  • Preferred ACE inhibitors are those agents that have been marketed, most preferred are benazepril and enalapril.
  • a diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon .
  • the most preferred diuretic is hydrochlorothiazide.
  • a diuretic furthermore comprises a potassium sparing diuretic such as amiloride or triameterine, or a pharmaceutically acceptable salt thereof.
  • the class of CCBs essentially comprises dihydropyridines (DHPs) and non- DHPs, such as diltiazem-type and verapamil-type CCBs.
  • DHPs dihydropyridines
  • non- DHPs such as diltiazem-type and verapamil-type CCBs.
  • a CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, a pharmaceutically acceptable salt thereof. All these CCBs are therapeutically used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs.
  • Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof.
  • DHP is amlodipine or a pharmaceutically acceptable salt thereof, especially the besylate.
  • An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
  • Beta-blockers suitable for use in the present invention include beta-adrenergic blocking agents (beta-blockers) , which compete with epinephrine for beta-adrenergic receptors and interfere with the action of epinephrine.
  • beta-blockers are selective for the beta-adrenergic receptor as compared to the alpha-adrenergic receptors, and so do not have a significant alpha-blocking effect.
  • Suitable beta-blockers include compounds selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol.
  • beta-blocker is an acid or base or otherwise capable of forming pharmaceutically acceptable salts or prodrugs
  • these forms are considered to be encompassed herein, and it is understood that the compounds may be administered in free form or in the form of a pharmaceutically acceptable salt or a prodrug, such as a physiologically hydrolyzable and acceptable ester.
  • a pharmaceutically acceptable salt or a prodrug such as a physiologically hydrolyzable and acceptable ester.
  • metoprolol is suitably administered as its tartrate salt
  • propranolol is suitably administered as the hydrochloride salt, and so forth.
  • Platelet aggregation inhibitors include PLAVIX® (clopidogrel bisulfate) , PLETAL® (cilostazol) and aspirin.
  • Cholesterol absorption modulators include ZETIA® (ezetimibe) and KT6-971 (Kotobuki Pharmaceutical Co. Japan).
  • HMG-Co-A reductase inhibitors also called beta-hydroxy-beta- methylglutaryl-co-enzyme-A reductase inhibitors or statins
  • statins are understood to be those active agents which may be used to lower lipid levels including cholesterol in blood.
  • the class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features.
  • the compounds which are selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or in each case, a pharmaceutically acceptable salt thereof .
  • HMG-Co-A reductase inhibitors are those agents, which have been marketed, most preferred is atorvastatin, pitavastatin or simvastatin, or a pharmaceutically acceptable salt thereof.
  • HDL-increasing compounds include, but are not limited to, cholesterol ester transfer protein (CETP) inhibitors.
  • CETP inhibitors include JTT7O5 disclosed in Example 26 of U.S. Patent No. 6,426,365 issued July 30, 2002, and pharmaceutically acceptable salts thereof.
  • Inhibition of interleukin 6 mediated inflammation may be achieved indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the signal transduction pathway utilizing interleukin-6 inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide (ASON), gpl30 protein inhibitor/antibody, tyrosine kinase inhibitors/antibodies, serine/threonine kinase inhibitors/antibodies, mitogen-activated protein (MAP) kinase inhibitors/antibodies, phosphatidylinositol
  • PI3K 3-kinase inhibitors/antibodies
  • Nuclear factor kappaB 3-kinase inhibitors/antibodies
  • NF-KB 1KB kinase
  • IKK 1KB kinase
  • API activator protein-1
  • STAT transcription factors inhibitors/antibodies altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, PPAR gamma and/or PPAR beta/delta activators/ligands or a functional fragment thereof.
  • a suitable antiinflammatory corticosteroid is dexamethasone .
  • Suitable antiproliferative agents are cladribine, rapamycin, vincristine and taxol.
  • a suitable inhibitor of extracellular matrix synthesis is halofuginone .
  • a suitable growth factor or cytokine signal transduction inhibitor is, e.g. the ras inhibitor R115777.
  • a suitable tyrosine kinase inhibitor is tyrphostin.
  • Suitable renin inhibitors are described, e.g. in WO 2006/116435.
  • a preferred renin inhibitor is aliskiren, preferably in the form of the hemi-fumarate salt thereof.
  • MCP-I antagonists may, e.g. be selected from anti-MCP-1 antibodies, preferably monoclonal or humanized monoclonal antibodies, MCP-I expression inhibitors, CCR2-antagonists, TNF- alpha inhibitors, VCAM-I gene expression inhibitors and anti-C5a monoclonal antibodies.
  • MCP-I antagonists and compositions containing such inhibitors are described, e.g. in WO 02/070509, WO 02/081463, WO 02/060900, US 2006/670364, US 2006/677365, WO 2006/097624, US 2006/316449, WO 2004/056727, WO 03/053368, WO 00/198289, WO 00/157226, WO 00/046195, WO 00/046196, WO 00/046199, WO 00/046198, WO 00/046197, WO 99/046991, WO 99/007351, WO 98/006703, WO 97/012615, WO 2005/105133, WO 03/037376, WO 2006/125202, WO
  • Suitable MCP-I antagonists are, for instance, C-243 (Telik Inc.); NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis Pharmaceuticals Inc.); ABN-912, NIBR-177 (Novartis AG); CC- 11006 (Celgene Corp.); SSR-150106 (Sanofi-Aventis) ; MLN-1202 (Millenium Pharmaceuticals Inc.); AGI-1067, AGIX-4207, AGI-1096 (AtherioGenics Inc.); PRS-211095, PRS-211092 (Pharmos Corp.); anti-C5a monoclonal antibodies, e.g.
  • neutrazumab G2 Therapies Ltd.
  • AZD-6942 AstraZeneca pic
  • 2-mercaptoimidazoles Johnson & Johnson
  • TEI-E00526, TEI-6122 Deltagen
  • RS-504393 Roche Holding AG
  • SB-282241, SB-380732, ADR-7 GaxoSmithKline
  • anti-MCP-1 monoclonal antibodies Johnson & Johnson
  • Combinations of QC-inhibitors with MCP-I antagonists may be useful for the treatment of inflammatory diseases in general, including neurodegenerative diseases.
  • Combinations of QC-inhibitors with MCP-I antagonists are preferred for the treatment of Alzheimer's disease.
  • the QC inhibitor is combined with one or more compounds selected from the following group: PF-4360365, m266, bapineuzumab, R-1450, Posiphen, (+) - phenserine, MK-0752, LY-450139, E-2012, (R) -flurbiprofen, AZD- 103, AAB-OOl (Bapineuzumab), Tramiprosate, EGb-761, TAK-070, Doxofylline, theophylline, cilomilast, tofimilast, roflumilast, tetomilast, tipelukast, ibudilast, HT-0712, MEM-1414, oglemilast, Linezolid, budipine, isocarboxazid, phenelzine, tranylcypromine, indantadol, moclobemide, rasagiline, ladostigil, sa
  • a QC inhibitor in particular QCI, in combination with Atorvastatin for the treatment and/or prevention of artherosclerosis
  • a QC inhibitor in particular QCI
  • immunosuppressive agents preferably rapamycin for the prevention and/or treatment of restenosis - a QC inhibitor, in particular QCI
  • immunosuppressive agents preferably paclitaxel for the prevention and/or treatment of restenosis
  • QC inhibitor in particular QCI
  • AChE inhibitors preferably Donepezil
  • QC inhibitor in particular QCI, in combination with interferones, preferably Aronex, for the prevention and/or treatment of multiple sclerosis - a QC inhibitor, in particular QCI, in combination with interferones, preferably betaferon, for the prevention and/or treatment of multiple sclerosis
  • a QC inhibitor in particular QCI, in combination with dexamethasone, for the prevention and/or treatment of atherosclerosis - a QC inhibitor, in particular QCI, in combination with dexamethasone, for the prevention and/or treatment of rheumatid arthritis
  • HMG-Co-A-reductase inhibitor in particular QCI, in combination with HMG-Co-A-reductase inhibitors, for the prevention and/or treatment of restenosis
  • the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin - a QC inhibitor, in particular QCI, in combination with HMG-Co-A reductase inhibitors, for the prevention and/or treatment of atherosclerosis
  • the HMG-Co-A- reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin
  • HMG-Co-A reductase inhibitor in particular QCI, in combination with HMG-Co-A reductase inhibitors, for the prevention and/or treatment of rheumatoid arthritis
  • HMG-Co-A- reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin
  • Such a combination therapy is in particular useful for AD, FAD, FDD and neurodegeneration in Down syndrome as well as atherosclerosis, rheumatoid arthritis, restenosis and pancreatitis .
  • Such combination therapies might result in a better therapeutic effect (less proliferation as well as less inflammation, a stimulus for proliferation) than would occur with either agent alone .
  • the present invention provides a method for preventing or treating a disease or condition, selected from a group consisting of inflammatory diseases selected from a. neurodegenerative diseases, e.g. mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, multiple sclerosis, b. chronic and acute inflammations, e.g. rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, c. fibrosis, e.g. lung fibrosis, liver fibrosis, renal fibrosis, d. cancer, e.g.
  • a disease or condition selected from a group consisting of inflammatory diseases selected from a. neurodegenerative diseases, e.g. mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, multiple sclerosis, b. chronic and acute inflammations, e.g
  • cancer/hemangioendothelioma proliferation gastric carcinomas, e. metabolic diseases, e.g. hypertension, f. and other inflammatory diseases, e.g. neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis.
  • metabolic diseases e.g. hypertension
  • f. and other inflammatory diseases e.g. neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis.
  • the present invention includes the use of the compounds of this invention and their corresponding pharmaceutically acceptable acid salt forms for the preparation of a medicament for the prevention or treatment of any of the above diseases or conditions.
  • the present QC inhibitors are used for the treatment of the above-mentioned neurodegenerative diseases. Even prefered is the use of the QC inhibitors of the present invention for the treatment of a disease selected from restenosis, pancreatitis, rheumatoid arthritis and atherosclerosis, most preferably restenosis or pancreatitis.
  • the compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal, parenteral and combinations thereof.
  • the invention relates to pharmaceutical compositions, that is to say, medicaments, that contain at least one compound of the invention or salts thereof, optionally in combination with one or more pharmaceutically acceptable carriers and/or solvents.
  • compositions may, for example, be in the form of parenteral or enteral formulations and contain appropriate carriers, or they may be in the form of oral formulations that may contain appropriate carriers suitable for oral administration. Preferably, they are in the form of oral formulations .
  • the inhibitors of QC activity administered according to the invention may be employed in pharmaceutically administrable formulations or formulation complexes as inhibitors or in combination with inhibitors, substrates, pseudosubstrates, inhibitors of QC expression, binding proteins or antibodies of those enzyme proteins that reduce the QC protein concentration in mammals.
  • the compounds of the invention make it possible to adjust treatment individually to patients and diseases, it being possible, in particular, to avoid individual intolerances, allergies and side-effects.
  • the compounds also exhibit differing degrees of activity as a function of time.
  • the physician providing treatment is thereby given the opportunity to respond differently to the individual situation of patients: he is able to adjust precisely, on the one hand, the speed of the onset of action and, on the other hand, the duration of action and especially the intensity of action .
  • the compounds may be advantageously administered, for example, in the form of pharmaceutical preparations that contain the active ingredient in combination with customary additives like diluents, excipients and/or carriers known from the prior art.
  • they can be administered parenterally (for example i.v. in physiological saline solution) or enterally (for example orally, formulated with customary carriers) .
  • one or more doses of the compounds can be given per day in order to achieve the desired reduction of MCP activity.
  • a dosage range in humans may be in the range of from about 0.01 mg to 250.0 mg per day, preferably in the range of about 0.01 to 100 mg of compound per kilogram of body weight per day.
  • the compounds used according to the invention can accordingly be converted in a manner known per se into conventional formulations, such as, for example, tablets, (bitable) capsules, dragees, pills, suppositories, granules, aerosols, syrups, drops, liquid, solid and cream-like emulsions and suspensions and/or also as suppositories or as nasal sprays solutions, using inert, non-toxic, pharmaceutically suitable carriers and additives or solvents.
  • the therapeutically effective compounds are preferably present in a concentration of approximately from 0.1 to 80% by weight, more preferably from 1 to 50% by weight, of the total mixture, that is to say, in amounts sufficient for the mentioned dosage latitude to be obtained.
  • the formulations may be advantageously prepared, for example, by extending the active ingredient with solvents and/or carriers, optionally with the use of emulsifiers and/or dispersants, it being possible, for example, in the case where water is used as diluent, for organic solvents to be optionally used as auxiliary solvents .
  • excipients useful in connection with the present invention include: water, non-toxic organic solvents, such as paraffins (for example natural oil fractions) , vegetable oils
  • solid carriers such as, for example, natural powdered minerals (for example highly dispersed silica, silicates) , sugars (for example raw sugar, lactose and dextrose) ; emulsifiers, such as non-ionic and anionic emulsifiers (for example polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylsulphonates and arylsulphonates) , dispersants (for example lignin, sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talcum, stearic acid and sodium lauryl sulphate) and optionally flavourings.
  • natural powdered minerals for example highly dispersed silica, silicates
  • sugars for example raw sugar, lactose and dextrose
  • emulsifiers such as non-ionic and anionic emulsifiers (for example polyoxy
  • Administration may be carried out in the usual manner, preferably enterally or parenterally, especially orally.
  • tablets may contain in addition to the mentioned carriers further additives such as sodium citrate, calcium carbonate and calcium phosphate, together with various additives, such as starch, preferably potato starch, gelatin and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulphate and talcum, can be used concomitantly for tabletting.
  • various taste correctives or colourings can be added to the active ingredients in addition to the above-mentioned excipients.
  • solutions of the active ingredients using suitable liquid carriers can be employed.
  • Pichia pastoris strain X33 (AOXl, A0X2), used for the expression of human QC was grown, transformed and analyzed according to the manufacturer's instructions (Invitrogen) . The media required for
  • P. pastoris i.e. buffered glycerol (BMGY) complex or methanol
  • the pQE-31 vector (Qiagen) was used to express the human QC in E. coll.
  • the cDNA of the mature QC starting with codon 38 was fused in frame with the plasmid encoded ⁇ xhistidine tag.
  • the fragment was inserted into the expression vector employing the restriction sites of Sphl and Hindlll.
  • Plasmid DNA was amplified in E. coll JM109 and purified according to the recommendations of the manufacturer (Qiagen) .
  • pPICZCCB three restriction sites are provided for linearization. Since Sad and BstXI cut within the QC cDNA, Pmel was chosen for linearization. 20-30 ⁇ g plasmid DNA was linearized with Pmel, precipitated by ethanol, and dissolved in sterile, deionized water. 10 ⁇ g of the DNA was then applied for transformation of competent P. pastoris cells by electroporation according to the manufacturer's instructions (BioRad) . Selection was done using plates containing 150 ⁇ g/ml Zeocin. One transformation using the linearized plasmid yielded several hundred transformants .
  • recombinant yeast clones were grown for 24 h in 10 ml conical tubes containing 2 ml BMGY. Afterwards, the yeast was centrifuged and resuspended in 2 ml BMMY containing 0.5 % methanol. This concentration was maintained by addition of methanol every 24 h up to 72 h. Subsequently, QC activity in the supernatant was determined. The presence of the fusion protein was confirmed by western blot analysis using an antibody directed against the ⁇ xhistidine tag (Qiagen) . Clones that displayed the highest QC activity were chosen for further experiments and fermentation.
  • the resulting eluate was dialyzed against 20 mM Bis-Tris/HCI, pH 6.8, at 4°C overnight. Subsequently, the QC was further purified by anion exchange chromatography an a Mono Q6 column (BioRad) , equilibrated with dialysis buffer. The QC-containing fraction was loaded onto the column using a flow rate of 4 ml/min. The column was then washed with equilibration buffer containing 100 mM NaCl. The elution was performed by two gradients resulting in equilibration buffer containing 240 mM and 360 mM NaCl in 30 or 5 column volumes, respectively.
  • the construct encoding the QC was transformed into M15 cells (Qiagen) and grown an selective LB agar plates at 37°C. Protein expression was carried out in LB medium containing 1% glucose and 1% ethanol at room temperature. When the culture reached an ODg QQ of approximately 0.8, expression was induced with 0,1 mM IPTG overnight. After one cycle of freezing and thawing, cells were lysed at 4°C by addition of 2.5 mg/ml lysozyme in 50 mM phosphate buffer, pH 8.0, containing 300 mM NaCl and 2 mM histidine for approximately 30 min.
  • the solution was clarified by centrifugation at 37000xg, 4 0 C for 30 min, followed by a filtration applying a glass frit (DNA separation) and two additional filtration steps applying cellulose filters for crude and fine precipitates.
  • the supernatant (approx. 500 ml) was applied onto a Ni2+-affinity column (1.6 x 20 cm) at a flow rate of 1 ml/min.
  • Elution of QC was carried out with 50 mM phosphate buffer containing 150 mM NaCl and 100 mM histidine.
  • the QC- containing fraction was concentrated by ultrafiltration.
  • Matrix-assisted laser desorption/ionization mass spectrometry was carried out using the Voyager De-Pro (Applied Biosystems, Darmstadt) with a linear time of flight analyzer. The instrument was equipped with a 337 nm nitrogen laser, a potential acceleration source and a 1.4 m flight tube. Detector operation was in the positive-ion mode. Samples (5 ⁇ l) were mixed with equal volumes of the matrix solution.
  • sinapinic acid prepared by solving 20 mg sinapinic acid (Sigma-Aldrich) in 1 ml acetonitrile/0.1% TFA in water (1/1, v/v) . A small volume ( ⁇ 1 ⁇ l) of the matrix-analyte-mixture was transferred to a probe tip.
  • a ⁇ -derived peptides were incubated in 100 ⁇ l 0.1 M sodium acetate buffer, pH 5.2 or 0.1 M Bis-Tris buffer, pH 6.5 at 30 0 C. Peptides were applied in 0.5 mM [A ⁇ 3-ll a] or 0.15 mM [A ⁇ 3-21a] concentrations, and 0.2 U QC was added all 24 hours. In case of A ⁇ 3-21a, the assays contained 1 % DMSO. At different times, samples were removed from the assay tube, peptides extracted using ZipTips
  • Human neuroblastoma cell line SH-SY5Y, human embryonic kidney cell line HEK293 and human monocyte cell line THP-I were cultured in appropriate cell culture media (DMEM, 10% FBS for SH-SY5Y and HEK293), (RPMI1640, 10 % FBS for THP-I), in a humidified atmosphere of 5% CO 2 (HEK293, THP-I) or 10% CO 2 (SH- SY5Y) at 37°C.
  • DMEM 10% FBS for SH-SY5Y and HEK293
  • RPMI1640 10 % FBS for THP-I
  • RNA of human MCP-I was isolated from SH-SY5Y cells using RT-PCR. Total RNA of SH-SY5Y cells was reversely transcribed by Superscript II (Invitrogen) and subsequently, human MCP-I was amplified on a 1:12,5 dilution of generated cDNA product in a 25 ⁇ l reaction with Pfu-DNA-Polymerase (Promega) using primers hMCP-1-1 (sense) and hMCP-1-2 (antisense) (Table 1) . The resulting PCR-product was cloned into vector pcDNA 3.1 using the HindIII and Notl restriction sites and the sequence confirmed by DNA-sequencing.
  • Site-directed mutagenesis of human MCP-I Deletions of the first ( ⁇ Q1) and first and second ( ⁇ Q1P2) amino acids of the mature human MCP-I were generated by site-directed mutagenesis using primer ⁇ Q1-1 and ⁇ Q1-2 for ⁇ Q1 (Table 1) and primers ⁇ Q1P2-1 and ⁇ Q1P2-2 for ⁇ Q1P2 (Table 1) .
  • Parental DNA was digested with Dpn I.
  • the pcDNA 3.1 plasmids with the deletions ⁇ Q1 and ⁇ Q1P2 of the mature human MCP-I were transformed into E. coli JM109. Ampicillin-resistant clones were confirmed by sequencing and subsequently isolated for cell culture purposes using the EndoFree Maxi Kit (Qiagen) .
  • N-terminal variants of human MCP-I in HEK293 cells
  • HEK293 cells were cultured in collagen I coated 6-well dishes and grown until 80% confluency, transfected using Lipofectamin2000 (Invitrogen) according to manufacturer's manual and incubated in the transfection solution for 5 hours. Afterwards, cells were allowed to recover in normal growth media over night. The next day, cells were incubated another 24 h in growth media. For analysis of efficacy of QC-inhibition, cells were incubated for 24 h in absence or presence of the specific inhibitor.
  • Lipofectamin2000 Invitrogen
  • the media containing the human MCP-I variants were collected and investigated in a migration assay for chemotactic potency. Furthermore, an aliquot of cell culture supernatant was stored at -80°C for quantification of human MCP-I concentration using a human MCP-I-ELISA (Pierce) .
  • the chemotaxis assay was performed using 24 well TransWell plates with a pore size of 5 ⁇ m (Corning) .
  • Media containing the human MCP-I variants expressed in HEK293 were used as chemoattractant .
  • 600 ⁇ l of the culture media of N-terminal human MCP-I variants was applied undiluted or in dilutions 1:3, 1:10 and 1:30 in RPMI1640 to the lower chamber of the TransWell plate.
  • undiluted media of HEK293 cells transfected with vector control were applied as negative control to the lower chamber.
  • THP-I cells were harvested and resuspended in RPMI1640 in a concentration of 1*10 ⁇ cells / 100 ⁇ l and applied in 100 ⁇ l aliquots to the upper chamber. Cells were allowed to migrate towards the chemoattractant for 2 h at 37 0 C. Subsequently, cells from the upper chamber were discarded and the lower chamber was mixed with 50 ⁇ l 70 mM EDTA in PBS and incubated for 15 min at 37°C to release cells attached to the membrane. Afterwards, cells migrated to the lower chamber were counted using a cell counter system (Scharfe System) . The chemotactic index was calculated by dividing cells migrated to the stimulus from cells migrated to the negative control.
  • Example 2 Investigations on the proteolytic degradation of human MCP-I (i-76)
  • Full length recombinant human MCP-I ( 1-76 ) (SEQ ID NO: 1) encoded by the nucleic acid sequence as shown in SEQ ID NO: 2, obtained in Example 1 above, starting with an N-terminal glutamine (Peprotech) was dissolved in 25 mM Tris/HCl pH 7.6 in a concentration of 10 ⁇ g/ml .
  • the MCP-I solution was either pre- incubated with recombinant human QC (0.0006 mg/ml) (obtained according to Reference Example 1 above, SEQ ID No: 3 for nucleic acid sequence and SEQ ID No: 4 for amino acid sequence) for 3 h at 30 0 C and subsequently incubated with recombinant human DP4
  • APMA enzyme-mixture of 10:1.
  • MCP-I was either pre-incubated with recombinant human QC (0.0006 mg/ml) for 3 h at 30 0 C and subsequently incubated with MMP-I at 30 0 C or incubated with MMP-I without prior QC application.
  • Resulting MMP-I cleavage products were analyzed after 0 min, 15 min, 30 min, Ih, 2h, 4h and 24 h using Maldi-TOF mass spectrometry.
  • MMP-I proenzyme from human rheumatoid synovial fibroblasts (Calbiochem) was activated using
  • the APMA enzyme-mixture of 10:1 was incubated at 37°C for 3h.
  • MCP-I solution was either pre-incubated with recombinant human QC (0.0006 mg/ml) for 3 h at 30 0 C and subsequently incubated with MMP-I and DP4 at 30 0 C or incubated with MMP-I and DP4 without QC application.
  • Resulting MMP-I cleavage products were analyzed after 0 min, 15 min, 30 min, Ih, 2h, 4h and 24 h using Maldi-TOF mass spectrometry.
  • Example 3 Effect of QC specific inhibitor 1- (3- (lH-imidazol-Ziyi) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydrochloride (in the following also designated as QCI) on cuff-induced accelerated atherosclerosis in ApoE3*Leiden mice
  • mice 30 male ApoE3*Leiden mice (age 12 weeks) were fed a mildly hypercholesterolemic diet for 3 weeks prior to surgical cuff placement .
  • mice After 3 weeks, the mice underwent surgical non-constricting cuff placement (day 0) and were divided into 2 groups, matched for plasma cholesterol levels. The mice either received control
  • mice were anaesthetized with an intraperitoneal injection of 5 mg/kg Dormicum, 0.5 mg/kg Domitor and 0.05 mg/kg Fentanyl .
  • This cocktail gives complete narcosis for at least one hour and can be quickly antagonized with Antisedan 2.5 mg/kg and Anexate 0.5 mg/kg.
  • a longitudinal 1 cm incision is made in the internal side of the leg and the femoral artery is dissected for 3 mm length from the femoral nerve and femoral vein.
  • the femoral artery is looped with a ligature and a non-constrictive fine bore polyethylene tubing (0.4 mm inner diameter, 0.8 mm outer diameter, length 2 mm) is longitudinally opened and sleeved loosely around the femoral artery.
  • the cuff is closed up with two ligature knots.
  • the skin is closed with a continued suture.
  • mice were sacrificed either 2 days or 14 days after cuff placement. After anaesthesia, the thorax was opened and a mild pressure-perfusion (100 mmHg) with 4% formaldehyde was performed for 3 minutes by cardiac puncture. After perfusion, a longitudinal 2 cm incision was made in the internal side of the leg and the cuffed femoral artery was harvested as a whole and fixed overnight in 4% formaldehyde and processed to paraffin.
  • a mild pressure-perfusion 100 mmHg
  • formaldehyde 4% formaldehyde
  • Adhesion of leukocytes in general and monocytes/macrophages in particular to the activated endothelium of the cuffed vessel wall was analyzed by microscopic analysis of cross sections harvested 2 days after cuff placement.
  • the number of adhering and/or infiltrating leukocytes in general, identified as adhering cells at the luminal side of the vessel segment, and monocytes/macrophages in particular was counted and illustrated as cells per cross-section or as defined areas per cross section.
  • Monocytes were identified by specific immunohistochemical staining by the polyclonal rabbit AIA31240 antibody, recognizing monocytes and macrophages. In addition on these sections a specific immunohistochemical staining for MCP-I was performed.
  • Vessel wall remodeling Analysis of vascular remodeling and accelerated athero-sclerosis Vessel wall remodeling, accelerated atherosclerosis and neoinitima formation were analyzed morphometrically in all mice sacrificed after 14 days. A full comparison between the two groups was performed for all relevant vessel wall parameters (neointima formation, vascular circumference (i.e. outward remodelling) , media thickness, lumen stenosis) . Accelerated atherosclerosis was analyzed by immunohistochemical staining for macrophages and foam cells in the lesion area by AIA31240 antibody. Furthermore, these sections were also stained for MCP- 1.
  • Example 4 Proteolytic degradation of human MCP-I ⁇ -76) by Dipeptidyl-peptidase 4 (DP4) , , Aminopeptidase P, and by proteases present in human serum
  • Recombinant human MCP-I ( i- ⁇ Q) (SEQ ID NO: 1) encoded by the nucleic acid sequence as shown in SEQ ID NO: 2, obtained in Example 1 above, starting with an N-terminal glutamine (Peprotech) was dissolved in 25 mM Tris/HCl pH 7.6 in a concentration of 10 ⁇ g/ml .
  • the MCP-I solution was either pre- incubated with recombinant human QC (0.0006 mg/ml) (obtained according to Reference Example 1 above) for 3 h at 30 0 C and subsequently incubated with recombinant human DP4 (0.0012 mg/ml) at 30 0 C (see Fig. 1) or incubated with DP4 without prior QC application.
  • MCP-I N-terminal degradation of human MCP-I in human serum
  • Human recombinant MCP-I carrying an N-terminal glutaminyl instead of a pyroglutamyl residue (Peprotech) was dissolved in 25 mM Tris/HCl, pH 7.6, in a concentration of 100 ⁇ g/ml.
  • MCP-I was either pre-incubated with recombinant human QC (0.006 mg/ml) for 3 h at 30 0 C and subsequently incubated with human serum at 30 °C or incubated with human serum without addition of QC.
  • the cleavage products were analyzed using Maldi-TOF mass spectrometry after 0 min, 10 min, 30 min, Ih, 2h, 3h 5h and 7 h for Glr ⁇ -MCP-l and 0 min, 30 min, Ih, 2h, 3h 5h, 7 h and 24 h for pGlu ⁇ MCP-l.
  • Example 5 Degradation of human MCP-2, MCP-3 and MCP-4
  • MCP-3 Human recombinant MCP-3 carrying an N-terminal glutaminyl instead of a pyroglutamyl residue (Peprotech) was dissolved in 25 mM Tris/HCl, pH 7.6, in a concentration of 10 ⁇ g/ml .
  • MCP-3 was either pre-incubated with recombinant human QC (0.0006 mg/ml) for 3 h at 30 0 C and subsequently incubated with recombinant human DP4 (0.00012 mg/ml) at 30 0 C or incubated with recombinant human DP4 (0.00012 mg/ml) without prior QC application.
  • Resulting DP4 cleavage products were analyzed using Maldi-TOF mass spectrometry after 0 min, 15 min, 30 min, Ih, 2h, 4h and 24 h.
  • N-terminal degradation of human MCP-4 by DP4 Human recombinant MCP-4 carrying an N-terminal glutaminyl instead of a pyroglutamyl residue (Peprotech) was dissolved in 25 mM Tris/HCl, pH 7.6, in a concentration of 10 ⁇ g/ml. MCP-4 was either pre-incubated with recombinant human QC (0.0006 mg/ml) for 3 h at 30 0 C and subsequently incubated with recombinant human DP4 (0.00006 mg/ml) at 30 °C or incubated with recombinant human DP4 (0.00006 mg/ml) without prior QC application. Resulting DP4 cleavage products were analyzed using Maldi-TOF mass spectrometry after 0 min, 15 min, 30 min, Ih, 2h, 4h and 24 h .
  • Example 6 Chemotactic Potency of different N-terminal variants of human MCP-I, MCP-2, MCP-3, MCP-4
  • Chemotactic Potency of N-terminal variants of human MCP-I MCP-I starting with glutamine 1 (Glr ⁇ -MCP-l) (Peprotech) was incubated with (i) recombinant human QC to generate pGlu 1 -MCP-l, (ii) human recombinant DP4 to generate Asp 3 -MCP-l, (iii) human synovial fibroblast MMP-I to generate Ile 5 -MCP-l and human recombinant Aminopeptidase P to generate Pro 2 -MCP-l.
  • the QC-inhibitor 1- (3- (lH-imidazol-1-yl) propyl) -3- (3, 4- dimethoxyphenyl) thiourea hydrochloride was formulated using 0.9% (w/v) saline at the highest concentration required. Lower doses were obtained by serial dilution using 0.9% (w/v) saline.
  • a stock solution (lmg/mL) of LPS was prepared using 0.9% (w/v) saline and diluted using 0.9% (w/v) saline to provide the required concentration for dosing.
  • Dose levels were expressed in terms of the amount of inhibitor administered without regard to purity or active content.
  • a terminal blood sample was collected at 2 hours post-LPS. Blood samples were centrifuged at 2300 x g for 10 minutes at 4°C and subsequently analyzed for TNFCC. Samples were analysed using a quantitative sandwich enzyme immunoassay.
  • Example 8 Evaluation of a QC-inhibitor in a mouse model of thioglycollate-induced peritonitis
  • mice were purchased from Charles River Laboratories Inc. For each experiment the mice were age- and sex-matched.
  • mice were injected i.p. with various concentrations of QC-inhibitor.
  • the animals were anesthesized using 2% isofluran.
  • Peritoneal exudates were collected at time points (4, 24 hours) after thioglycollate injection by washing the peritoneum with 8 ml of sterile phosphate-buffered saline (PBS) . Subsequently, the lavage fluids were centrifuged to pellet the cells and stained for FACS analysis.
  • PBS sterile phosphate-buffered saline
  • CD3-FITC (Caltag) /CD13-PE (BD) /F4/80-APC (Caltag); Moma2-FITC
  • Purified human MCP-I displays a bell-shaped chemotactic dose response curve, when attracting, e.g. monocytes, showing an optimum at approx. 1-50 ng/ml . Therefore, the generated cell culture supernatants containing MCP 1 variants were sequentially diluted in order to achieve the optimal working concentration of MCP-I for chemotaxis assay attracting THP-I monocytes. After expression of MCP-I (WT) and MCP-I ( ⁇ Q1), the concentrations of MCP-I variants did not significantly differ (Figure 5C) .
  • MCP-I is protected by a N-terminal pGlu- residue, which confers resistance against N-terminal cleavage by aminopeptidases, e.g. DP4.
  • N-terminal truncation leads to inactivation of human MCP-I ( Figure 5 and 6) .
  • MMP-I inactivates mature MCP-I by cleavage of the 4 N-terminal amino acids (pE/Q-P-D-A) .
  • the reaction is independent from the presence of a N-terminal pGlu residue. This process reflects the situation of MCP-I inactivation within the circulation.
  • the resulting cleavage product MCP 1 ( 5-75 ) has been shown to be present within plasma and resembles a naturally occurring CCR2 receptor antagonist.
  • the present experiments point to the finding that MMP-I cleavage is slightly faster in case of a N-terminal glutamine residue (Figure 2A: 2h, 4h vs. 2B: 2h, 4h) .
  • N-terminal pGlu formation represents a mechanism of protection, conferring resistance against N-terminal degradation by post-proline cleaving enzymes, e.g. DP4, aminopeptidases and, as implied by the results with MMP-I, to a certain extent also endoproteases .
  • DP4 post-proline cleaving enzymes
  • MMP-I aminopeptidases
  • MCP-I expression was reduced in the vessel segments of 1-(3-(1H- imidazol-1-yl) propyl) -3- (3, 4-dimethoxyphenyl) thiourea hydrochloride treated mice 2 days after surgery, the moment of the highest elevation of MCP-I expression in the model used
  • aminopeptidase P cleaves between the N- terminal amino acids GIn 1 and Pro 2 and liberates the N-terminal glutaminyl residue ( Figure 16 A) .
  • pre-incubation of Gln 1 -MCP-l with human QC causes the formation of the N-terminal pGlu-residue and, therefore, the protection against aminopeptidase P cleavage ( Figure 16 B).
  • the formation of the N-terminal pGlu-residue is also a protection mechanism against aminopeptidase P cleavage and against the cleavage of presumably all other proline-specific aminopeptidases .
  • the uncyclized variants starting with an N-terminal glutamine are readily truncated by DP4 as shown for Gln 1 -MCP-2 ( Figure 19 A), Glr ⁇ -MCP- 3 ( Figure 20 A) and Gln 1 -MCP-4 ( Figure 21 A) . Therefore, the N- terminal pGlu-residue stabilizes all MCPs against truncation by aminopeptidases, such as DP4.
  • the presented concept to reduce QC acitivity in vivo in order to provoke accelerated turnover and diminished chemotaxis and receptor activation, applies for all members of the MCP-family.
  • MCP-I The full-length MCP-I possessing an N-terminal glutaminyl or pyroglutamyl-residue were found to be equally potent in attracting THP-I monocytes with a maximum response between 50 ng/ml and 100 ng/ml .
  • the truncation of MCP-I by aminopeptidase P (Pro 2 -MCP-l) and DP4 (Asp 3 -MCP-l) leads to a loss of potency of the respective variant.
  • the dose- response-curve shifts to higher concentrations needed to elicit the maximum response, which corresponds to an inactivation of MCP-I by N-terminal truncation.
  • the MMP-I cleavage product (He 5 - MCP-I) has an equal maximum as Glu 1 -MCP-l and pGlu 1 -MCP-l between 50 ng/ml and 100 ng /ml, however, the amount of cells migrating to this variant, ie. the chomotactic potency, is much lower, compared to full-length MCP-I ( Figure 22) .
  • Gln 1 -MCP-l was incubated with human DP4.
  • MCP-I was pre- incubated with human QC prior to DP4 application.
  • the obtained dose-response curves imply a proteolytic stability of pGlu 1 -MCP-l reflected by a maximum response at 50 - 100 ng / ml.
  • Gln 1 -MCP-l is truncated by DP4, which leads to a shift of the dose-response curve to higher MCP-I concentrations (500-1000 ng / ml) needed to elicit the maximum response.
  • the inhibition of QC leads to the N-terminal destabilization of MCP-I through degradation by DP4 and, thus, to its inactivation with respect to the monocyte chemotactic activity.
  • MCP-2, MCP-3 and MCP-4 possessing an N-terminal glutamine or pyroglutamate to attract human THP-I monocytes was investigated.
  • the pGlu-formation at the N-terminus of MCP-2 and MCP-3 has no influence on the potency, compared to the respective glutamine-precursors .
  • the pGlu-formation slightly increases the potency of the peptide ( Figure 24) .
  • Synthesis scheme 1 Synthesis of the examples 1-53, 96-102, 136- 137
  • Reagents and conditions (a) NaH, DMF, 4h, rt . ; (b) , 8h, 100 0 C; (c) H 2 N-NH 2 , EtOH, 8h, reflux then 4N HCl, 6h, reflux, (d) R 3 -NCO, EtOH, 6h, reflux, (e) 3,4 dimethoxy-phenyl-isothiocyanate, Synthesis scheme 2 : Synthes i s of the examples 54 - 95
  • Reagents and conditions (a) R-NCS, EtOH, 6h, reflux; (b) WSCD, lH-imidazole-1-propanamine, DMF, 2h, r.t.
  • Synthesis scheme 3 Synthesis of the examples 103-105
  • Reagents and conditions (a) NaH, DMF, rt.,3h; (b) LiAlH 4 , dioxane, reflux, Ih; (c) R-NCS, EtOH, reflux 6h,
  • Synthesis scheme 4 Synthesis of the examples 106 - 109
  • Synthesis scheme 6 Synthesis of the examples 113 -132
  • Synthesis scheme 7 Synthesis of the examples 133 - 135
  • Synthesis scheme 11 Synthesis of the example 141
  • Reagents and conditions (a) NaH, DMF, 4h, rt.; (b) , 8h, 100 0 C; (c) H 2 N-NH 2 , EtOH, 8h, reflux then 4N HCl, 6h, reflux, (d) 3,4 dimethoxy-phenyl-isothiocyanate, EtOH, 6h, reflux
  • Splitting patterns have been designated as follows: s (singulet) , d (doublet) , dd (doublet of doublet) , t (triplet) , m (multiplet) , and br (broad signal) .
  • Examples 1 - 12 and 14 - 53 lH-imidazole-1-propanamine was reacted with the corresponding isothiocyanate in ethanol under reflux for 8h. After that the solvent was removed and the remaining oil was dissolved in methylene chloride. The organic layer was washed twice with a saturated solution of NaHC ⁇ 3 followed by NaHSO 4 and brine, dried then evaporated. The remaining solid was re-crystallized from ethyl acetate, yielding the example thiourea in yields of 80 - 98%.
  • Examples 96 - 102 lH-imidazole-1-propanamine was reacted with the corresponding isocyanate in ethanol under reflux for 8h. After that the solvent was removed and the remaining oil was dissolved in methylene chloride. The organic layer was washed twice with a saturated solution of NaHCO 3 followed by NaHSO 4 and brine, dried then evaporated. The remaining solid was re-crystallized from ethyl acetate, yielding the example urea in yields of 85 - 90%.
  • the lH-imidazole-1-alkylamines were prepared according to the literature from -brom-alkyl-phtalimides and imidazolium salt and. subsequent hydrazinolysis .
  • the resulting products were transformed into the thioureas according to example 1 - 53 giving a 88% (example 136) and 95% (example 137) yield.
  • Examples 103 - 105 Imidazole was reacted with the corresponding brommethylphenylcyanide in DMF, utilizing 1 equivalent of NaH for 3h under rt., giving the lH-imidazole-1- methylphenylcyanides .
  • the solvent was removed and the resulting oil was re-dissolved in dioxane.
  • the cyanides were converted in the corresponding amines using 1 equivalent of LiAlH 4 .
  • dioxane was evaporated and the aqueous layer was extracted by means of CHCI3.
  • the organic layer was concentrated in vacuo and the amine was converted in the corresponding thioureas according to example 1 — 53 giving a 78% (example 103) and 65% (example 104) and 81% (example 105) yield.
  • Examples 110 - 112 lH-imidazole-1-propanamine was reacted with the corresponding 2- chlorobenzo [d] thiazole in toluol for 24h at a temperature of 130 0 C. After removing the solvent and recristallization from methanol example 110 - 112 was yielded in an amount of 55 - 65%.
  • Examples 113 - 118, 120 - 124 and 126 - 132 lH-imidazole-1-propanamine was reacted with the corresponding 2- phenyl acetic acid in dry dioxane by adding one equivalent of CAIBE and N-methylmorpholine at a temperature of 0 0 C. After 2h the mixture was allowed to warm to r.t. and the mixture was stirred for 12h. After removing the solvent the resulting oil was redissolved in methylene chloride and the organic layer was washed by means of an aqueous solution of NaHC ⁇ 3 and water, dried and the solvent was evaporated. The remaining oil was dissolved in dioxane adding Laweson's Reagent.
  • the organic solution was dried, filtered, and the solvent was removed under reduced pressure. After redissolving in 50 mL of dry dioxane 2.2 mmol of Lawesson' s reagent was added, and the mixture was heated to 90 0 C and stirred for 8 h. The solvent was removed by reduced pressure, and the residue was redissolved in 50 mL of dichloromethane. The organic layer was washed three times by means of a saturated aqueous solution of NaHC ⁇ 3, followed three times by water, dried, filtered, and then the organic solvent was removed.
  • the compound was purified by chromatography using a centrifugal-force-chromatography device, (Harrison Research Ltd.) utilizing silica plates of a layer thickness of 2 mm, and a CHCl 3 /MeOH gradient as eluting system.
  • Examples 133 - 135 A mixture of 1 equivalent triethylamine and 3, 4-dimethoxyaniline in dioxane was added to an stirred solution of the corresponding C ⁇ -bromoalkyl acidic chloride at a temperature of 0 0 C. The solution was allowed to warm to r.t. and stirred for 2h. The solvent was evaporated, and the remaining oil was redissolved in dichloromethane . The organic layer was washed by means of water, dried, filtered, and the solvent was removed under reduced pressure.
  • Example 1 1- (3- (lH-imidazol-1-yl)propyl) -3-methylthiourea melting point: 122 - 122.5°C
  • Example 3 1- (3- (lH-imidazol-1-yl)propyl) -3-benzylthiourea melting point: 127.0 - 128.0 0 C
  • Example 5 1- (3- ( IH- lmldazol-1-yl) propyl) -3 -phenyl thiourea melting point: 166.5 - 167.0 0 C
  • Example 6 1- (3- (lH-imidazol-1-yl)propyl) -3- (4- fluorophenyl) thiourea melting point: 147.0 - 148.0°C
  • Example 7 1- (3- (lH-imidazol-1-yl)propyl) -3- (4- ethylphenyl) thiourea melting point: 100.0 - 100.5 0 C
  • Example 8 1- (3- (lH-imidazol-1-yl)propyl) -3- (4- (trifluoromethyl)phenyl) thiourea melting point: 154.5 - 155.0 0 C
  • Example 10 1- (3- (lH-imidazol-1-yl)propyl) -3- (4- acetylphenyl) thiourea melting point: 170.0 - 171.0 0 C 1H NMR ⁇ 1.9 - 2.1 (br m, 2H), 2.4 - 2.5 (s, 3H), 3.2 - 3.5 (br m, 2H), 3.9 - 4.1 (m, 2H), 6.85 (d, IH), 7.15 (d, IH), 7.5 - 7.65 (br m, 3H), 7.8 - 7.9 (m, 2H), 8.1 (m, 2H), 9.8 (br s, IH); MS m/z 303.2 (M+H), 235.1 (M-C 3 H 3 N 2 O
  • Example 11 1- (3- (lH-imidazol-1-yl)propyl) -3- (4- methoxyphenyl) thiourea melting point: 125.0 - 125.5°C
  • Example 14 1- (3- (lH-imidazol-1-yl)propyl) -3- (2, 4- dimethoxyphenyl) thiourea melting point: 120.0 - 120.5 0 C
  • Example 15 1- (3- (lH-imidazol-1-yl)propyl) -3- (3, 5- dimethoxyphenyl) thiourea melting point: 142.0 - 143.0 0 C
  • Example 23 1- (3- (lH-imidazol-1-yl)propyl) -3- (2, 3- dihydrobenzo [b] [1 , 4] dioxin-7-yl) -thiourea melting point: 103.0 - 103.5 0 C 1H NMR ⁇ 1.9 - 2.0 (br m, 2H), 3.3 - 3.5 (br d, 2H), 3.9 - 4.0
  • Example 25 1- (3- (lH-imidazol-1-yl)propyl) -3- (3, 4 , 5- trimethoxyphenyl) thiourea melting point: 124.5 - 125.5°C
  • Example 26 1- (3- (lH-imidazol-1-yl)propyl) -3- (3- methoxyphenyl) thiourea melting point: 89.5 - 90.0 0 C
  • Example 27 1- (3- (lH-imidazol-1-yl)propyl) -3- (4- ethoxyphenyl) thiourea melting point: 126.0 - 126.5°C 1H NMR ⁇ 1.5 (br m, 3H), 1.9 - 2.0 (br m, 2H), 3.4 - 3.5 (br m, 2H), 3.9 - 4.0 (br m, 4H), 6.8 - 6.9 (m, 2H), 6.95 (s, IH), 7.15 - 7.2 (m, 2H), 7.25 (s, IH), 7.55 - 7.6 (br s, IH), 7.8 (s, IH), 9.3 (s, IH); MS m/z 305.2 (M+H), 237.2 (M-C 3 H 3 N 2 *)
  • Example 42 1- (3- (lH-imidazol-1-yl)propyl) -3- (4- nitrophenyl) thiourea melting point: 165.0 . 166.0 0 C
  • Example 50 1- (3- (lH-imidazol-1-yl) propyl) -3- (4- (dimethylamino) phenyl) thiourea melting point: 146.5 - 147.0 0 C
  • Example 102 1- (3- (lH-imidazol-1-yl)propyl) -3- (3, 4- dimethoxyphenyl) urea melting point: 114.5 - 115.0 0 C 1H NMR ⁇ 1.7 - 1.9 (m, 2H), 2.9 - 3.1 (m, 2H), 3.7 (2s, 6H), 3.9 - 4.0 (m, 2H), 6.1 (t, IH), 6.7 (s, 2H), 6.8 (s, IH), 7.15 (d, 2H), 7.6 (s, IH), 8.2 (s, IH); MS m/z 321.2 (M+H), 253.3 (M- C 3 H 3 N 2 *)
  • Example 106 1- ( (S) -3- (lH-imidazol-1-yl) -2-methylpropyl) -3- (3, 4- dimethoxyphenyl) -thiourea melting point:: 150.5 - 151.5°C
  • Example 107 1- ( (R) -3- (lH-imidazol-1-yl) -2-methylpropyl) -3- (3, 4- dimethoxyphenyl) -thiourea melting point: 155.0 - 157.5 0 C
  • Example 109 1- ( (1- ( (lH-lmldazol-1- yl) methyl) cyclopropyl) methyl) -3- (3, 4-dlmethoxy-phenyl) thiourea melting point: 166.5 - 168.5°C
  • Example 121 N- (3- (lH-lmldazol-1-yl)propyl) -1- (4- chlorophenyl) cyclobutanecarbo-thloamide melting point: 137.5 - 139.0 0 C 1H NMR ⁇ 1.55 - 1.75 (br m, 2H) , 1.85 - 1.95 (br m, 2H) , 2.4 - 2.5 (br m, 2H) , 2.7 - 2.85 (br m, 2H) , 3.3 - 3.5 (br m, 2H) , 3.8 (m, 2H) , 6.9 (s, IH) , 7.0 (s, IH) , 7.3 (m, 2H) , 7.45 (s, IH) , 7.5 (m, 2H) , 9.6 (t, IH) ; MS m/z 334.3 (M+H) , 266.1 (M-C 3 H 3 N 2 O
  • Example 122 N- (3- (lH-lmldazol-1-yl) propyl) -1- (4- chlorophenyl ) cycl open tanecarbo-thloaml de melting point: 140.0 - 141.0 0 C 1 H NMR ⁇ 1.5 - 1.65 (br m, 4H), 1.8 - 1.9 ( m, 2H), 2.0 - 2.1 (m, 2H), 2.6 (m, 2H), 3.4 - 3.5 (m, 2H), 3.7 - 3.8 (m, 2H), 6.85 (s, IH), 7.0 (s, IH), 7.35 (m, 2H), 7.4 (m, 2H), 7.5 (s, IH), 9.4 (t, IH); MS m/z 348.2 (M+H) , 280.2 (M-C 3 H 3 N 2 O
  • Example 123 N- (3- (lH-imidazol-1-yl)propyl) -1- (4- methoxyphenyl) cyclohexanecarbo-thioamide melting point: 162.5 - 164.0 0 C
  • Example 124 N- (3- (lH-imidazol-1-yl)propyl) -1- (4- methoxyphenyl) cyclopropanecar-bothloamlde melting point:: 129.0 - 129.5°C
  • Example 134 5- (lH-imidazol-1-yl) -N- (3, 4- dimethoxyphenyl)pentanethioamide melting point:: 128.0 - 128.5°C 1H NMR ⁇ 1.65 - 1.70 (m, 2H), 1.75 - 1.80 (m, 2H), 2.7 - 2.75 (m, 2H), 3.7 (s, 3H), 3.75 (s, 3H), 4.0 - 4.05 (t, 2H), 6.9 - 7.0 (m, 2H), 7.2 (s, IH), 7.3 (d, IH), 7.5 (s, IH), 7.75 (s, IH), 11.0 (s, IH); MS m/z 320.2 (M+H), 252.2 (M-C 3 H 3 N 2 O
  • Example 136 1- (2- (lH-imidazol-1-yl) ethyl) -3- (3, 4- dlmethoxyphenyl) thiourea melting point: 157.5 - 159.0 0 C 1 H NMR ⁇ 3.7 (2 s, 6H), 3.8 (m, 2H), 4.2 (m, 2H), 6.7 (m, IH), 6.85 (m, IH), 6.9 (m, 2H), 7.15 (s, IH), 7.5 (br s, IH), 7.6 (s, IH), 9.5 (s, IH); MS m/z 307.2 (M+H) , 239.1 (M-C 3 H 3 N 2 ')

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0808170A2 (pt) * 2007-03-01 2014-07-08 Probiodrug Ag Uso de inibidores de glutaminil ciclase
UA108742C2 (uk) * 2009-09-23 2015-06-10 Фармацевтична композиція для лікування запальних захворювань, опосередкованих mcp-1
SG182615A1 (en) * 2010-02-18 2012-08-30 Probiodrug Ag Methods of diagnosing inflammatory diseases by determining pyroglutamate-modified mcp-1 and screening methods for inhibitors of glutaminyl cyclase
CN105384692B (zh) * 2015-10-26 2018-06-29 深圳大学 一种谷氨酰胺酰基环化酶抑制剂
CN105384691B (zh) * 2015-10-26 2018-06-29 深圳大学 一种谷氨酰胺酰基环化酶抑制剂的制备方法及应用
DK3658141T3 (da) * 2017-07-24 2023-02-06 Stichting Het Nederlands Kanker Inst Antoni Van Leeuwenhoek Ziekenhuis Behandling af patologiske tilstande ved direkte og indirekte målretning af Sirpalpha-CD47-interaktion
KR102230832B1 (ko) * 2019-06-17 2021-03-24 (주) 메디프론디비티 N-치환된 티오우레아 또는 우레아 유도체 및 이를 유효성분으로 함유하는 글루타미닐 사이클레이즈 활성 관련 질환의 예방 또는 치료용 약학적 조성물
AU2022298746A1 (en) 2021-06-24 2023-11-30 Insilico Medicine Ip Limited Beta-lactam derivatives for the treatment of diseases

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5100909A (en) * 1988-07-25 1992-03-31 The Upjohn Company Acetylenic imidazoles having central nervous system activity
WO1997043278A1 (en) * 1996-05-14 1997-11-20 Novo Nordisk A/S Somatostatin agonists and antagonists
WO2002096869A2 (en) * 2001-05-29 2002-12-05 Peking University School Of Pharmaceutical Sciences Piperazine mono(dithio)carbamate ester compounds and analogs thereof
WO2003022273A1 (en) * 2001-09-13 2003-03-20 Boehringer Ingelheim Pharmaceuticals, Inc. Methods of treating cytokine mediated diseases
US20030166644A1 (en) * 2001-12-14 2003-09-04 Soren Ebdrup Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
US20070191366A1 (en) * 2003-05-05 2007-08-16 Torsten Hoffmann Use of effectors of glutaminyl and glutamate cyclases

Family Cites Families (429)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5736816A (ja) 1980-08-14 1982-02-27 Toshiba Corp Chodendokoirunoseizohoho
JPS57192573A (en) 1981-05-25 1982-11-26 Hochiki Co Fire fighting agent
EP0117462A3 (en) 1983-02-28 1986-08-20 American Cyanamid Company N-(2-4-(1h-imidazol-1-yl)alkyl)arylamides
JPS60165712A (ja) 1984-02-08 1985-08-28 パイオニア株式会社 可変調整部品の自動調整方法
JPS6126111A (ja) 1984-07-16 1986-02-05 Shin Meiwa Ind Co Ltd 産業用ロボツト
JPS6137764A (ja) 1984-07-31 1986-02-22 Suntory Ltd 抗プロリルエンドペプチダ−ゼ活性を有する新規生理活性化合物
JPS6152021A (ja) 1984-08-22 1986-03-14 Fujitsu Ltd スケルチ回路
JPS6172439A (ja) 1984-09-18 1986-04-14 Sanyo Electric Co Ltd デ−タ転送方式
DE3684633D1 (de) 1985-04-16 1992-05-07 Suntory Ltd Dipeptid-derivate von fettsaeure, verfahren zu ihrer herstellung, heilmittel, das sie enthaelt und anwendung.
JPH0623190B2 (ja) 1985-04-16 1994-03-30 サントリー株式会社 インヒビタ−活性を有するｎ−アシルピロリジン誘導体及びその製法並びに用途
US4873342A (en) 1985-04-16 1989-10-10 Suntory Limited Dipeptide derivative and synthesis and use thereof
JPS62114957A (ja) 1985-11-13 1987-05-26 Suntory Ltd プロリルエンドペプチダ−ゼ阻害作用を有する新規ピロリジン誘導体およびその製法並びに用途
JPH0714878B2 (ja) 1985-11-14 1995-02-22 サントリー株式会社 ピロリジンアミドを有効成分とするプロリルエンドペプチダーゼ阻害剤
JPH0764834B2 (ja) 1985-11-29 1995-07-12 サントリー株式会社 プロリルエンドペプチダーゼ阻害活性を有する新規ピロリジンアミド誘導体およびその製法並びに用途
US5198458A (en) 1986-02-04 1993-03-30 Suntory Limited Pyrrolidineamide derivatives of acylamino acid and pharmaceutical composition containing the same
CA1320734C (en) 1986-02-04 1993-07-27 Suntory Limited Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same
CA1334092C (en) 1986-07-11 1995-01-24 David John Carini Angiotensin ii receptor blocking imidazoles
JPS6386485A (ja) 1986-09-30 1988-04-16 Agency Of Ind Science & Technol トンネル型ジヨセフソン接合素子
US5223482A (en) 1986-11-17 1993-06-29 Scios Nova Inc. Recombinant Alzheimer's protease inhibitory amyloid protein and method of use
JPH08806B2 (ja) 1986-11-18 1996-01-10 サントリー株式会社 プロリルエンドペプチダ−ゼ阻害作用を有する新規ピロリジンアミド誘導体
US5254550A (en) 1986-11-20 1993-10-19 Ono Pharmaceutical Co., Ltd. Prolinal derivatives and pharmaceutical compositions thereof
DE3786229T2 (de) 1986-11-20 1993-10-07 Ono Pharmaceutical Co Prolinalderivate.
JPS63162672A (ja) 1986-12-25 1988-07-06 Ono Pharmaceut Co Ltd 新規なプロリナ−ル誘導体、それらの製造方法およびそれらを含有する抗健忘症剤
ATE84787T1 (de) 1986-12-29 1993-02-15 Ono Pharmaceutical Co Prolin-derivate.
US5262431A (en) 1986-12-29 1993-11-16 Ono Pharmaceutical Co., Ltd. Prolinal derivatives and pharmaceutical compositions thereof
JPH089591B2 (ja) 1986-12-29 1996-01-31 小野薬品工業株式会社 新規なプロリナール誘導体
EP0277588B1 (en) 1987-02-04 1993-03-24 Ono Pharmaceutical Co., Ltd. Prolinal derivatives
JP2528343B2 (ja) 1987-02-04 1996-08-28 小野薬品工業株式会社 新規なプロリナ―ル誘導体
DE3875361T2 (de) 1987-02-23 1993-03-25 Ono Pharmaceutical Co Thiazolidin-derivate.
JPS6442465A (en) 1987-08-07 1989-02-14 Wakunaga Pharma Co Ltd N-acylprolylpyrrolidine derivative, production and use thereof
US4857524A (en) 1987-08-08 1989-08-15 Kissei Pharmaceutical Co., Ltd. Thiazolidine compounds and therapeutic method
JP2649237B2 (ja) 1988-03-07 1997-09-03 キッセイ薬品工業 株式会社 チアゾリジン誘導体
JP2515558B2 (ja) 1987-09-10 1996-07-10 株式会社ヤクルト本社 新規なペプチドおよびそれを有効成分とする抗健忘症剤
CA1339014C (en) 1987-10-08 1997-03-25 Ronald E. Majocha Antibodies to a4 amyloid peptide
JPH0742309B2 (ja) 1987-11-30 1995-05-10 キッセイ薬品工業株式会社 チアゾリジン誘導体
JPH01250370A (ja) 1987-12-23 1989-10-05 Zeria Pharmaceut Co Ltd 新規アミノ酸イミド誘導体、製法ならびに用途
US5053414A (en) 1988-04-08 1991-10-01 Ono Pharmaceutical Co., Ltd. Heterocyclic compounds
US5328899A (en) 1988-07-15 1994-07-12 The Salk Institute For Biological Studies NPY peptide analogs
ZA896374B (en) 1988-08-26 1990-05-30 Merrell Dow Pharma Neuropeptide y antagonists
ZA896376B (en) 1988-08-26 1990-05-30 Merrell Dow Pharma Neuropeptide y agonists
JP2531989B2 (ja) 1988-09-14 1996-09-04 吉富製薬株式会社 ピリジン化合物
CA2004028C (en) 1988-12-08 1998-09-22 Motoki Torizuka Condensed benzene derivative
JPH02207070A (ja) 1989-02-07 1990-08-16 Zeria Pharmaceut Co Ltd アミノ酸イミド誘導体、それを含有する医薬及び該化合物の製造中間体
EP0419683A4 (en) 1989-04-13 1992-03-11 Japan Tobacco Inc. New amino acid derivatives having prolylendopeptidase inhibitor activity
AU5439790A (en) 1989-04-14 1990-11-16 Research Foundation For Mental Hygiene, Inc. Cerebrovascular amyloid protein-specific monoclonal antibody sv17-6e10
AU5525090A (en) 1989-04-14 1990-11-16 Research Foundation For Mental Hygiene, Inc. Monoclonal antibody to amyloid peptide
ATE190051T1 (de) 1989-06-14 2000-03-15 Smithkline Beecham Corp Imidazoalkensäure
JPH082791B2 (ja) 1989-07-24 1996-01-17 キッセイ薬品工業株式会社 健忘症治療剤
DE3939797A1 (de) 1989-12-01 1991-06-06 Basf Ag Neue vom neuropeptid y abgeleitete peptide
US4985560A (en) 1990-01-12 1991-01-15 American Home Products Corporation Pyridazino(4,5-b)indolizines
DE122010000024I1 (de) 1990-02-19 2010-07-08 Novartis Ag Acylverbindungen
JPH04211648A (ja) 1990-07-27 1992-08-03 Nippon Kayaku Co Ltd ケト酸アミド誘導体
JPH03255080A (ja) 1990-03-05 1991-11-13 Yoshitomi Pharmaceut Ind Ltd ベンゼン化合物
PT97078B (pt) 1990-03-20 1997-07-31 Sanofi Sa Processo para a preparacao de derivados heterociclicos n-substituidos e de composicoes farmaceuticas que os contem
US5073549A (en) 1990-03-22 1991-12-17 Bristol-Myers Squibb Company BU-4164E - A and B, prolyl endopeptidase inhibitors and their methods of use
US4999349A (en) 1990-03-22 1991-03-12 Bristol-Myers Squibb Co. BU-4164E - A and B, prolyl endopeptidase inhibitors
US5196444A (en) 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
EP0536163A1 (en) 1990-06-04 1993-04-14 Pfizer Inc. Aromatic pyrrolidine and thiazolidine amides
US5407950A (en) 1990-06-07 1995-04-18 Zeria Pharmaceutical Co., Ltd. Arylalkanoylamine derivative and drug containing the same
US5506256A (en) 1990-07-27 1996-04-09 Yoshitomi Pharmaceutical Industries, Ltd. Proline derivatives possessing prolyl endopeptidase-inhibitory activity
EP0468469A2 (en) 1990-07-27 1992-01-29 Japan Tobacco Inc. Proline derivatives
JPH05186498A (ja) 1991-12-27 1993-07-27 Japan Tobacco Inc プロリン誘導体
JPH04235162A (ja) 1990-08-09 1992-08-24 Zeria Pharmaceut Co Ltd 新規コハク酸アミド誘導体およびそれを含有する医薬
JPH04208299A (ja) 1990-11-30 1992-07-29 Ajinomoto Co Inc プロリルエンドペプチターゼ阻害ペプチド
IE920540A1 (en) 1991-02-21 1992-08-26 Sankyo Co 1-biphenylmethylimidazole derivatives, their preparation and¹their therapetuic use
US5104880A (en) 1991-05-01 1992-04-14 Mayo Foundation For Medical Education And Research Huperzine a analogs as acetylcholinesterase inhibitors
WO1992021333A2 (en) 1991-05-24 1992-12-10 Pharmavene, Inc. Treatment of drug withdrawal symptoms and drug craving with type b monoamine oxidase inhibitors
ATE157988T1 (de) 1991-06-20 1997-09-15 Snow Brand Milk Products Co Ltd Neuartige prolyl-endopeptidase-inhibitoren sna- 115 und sna-115t, ihre herstellung, und hierbei verwendete stämme
DE4121975A1 (de) 1991-07-03 1993-01-07 Basf Ag Thermoplastische formmassen auf der basis von polycarbonaten, styrol/acrylnitril-polymerisaten und polyolefinen
CA2113115A1 (en) 1991-07-29 1993-02-18 Vlad E. Gregor Quinazoline derivatives as acetylcholinesterase inhibitors
TW226375B (OSRAM) 1991-10-24 1994-07-11 American Home Prod
WO1993012139A1 (en) 1991-12-19 1993-06-24 Garvan Institute Of Medical Research A novel molecule which inhibits neuropeptide tyrosine biological function
JPH05301826A (ja) 1991-12-24 1993-11-16 Snow Brand Milk Prod Co Ltd プロリルエンドペプチダーゼ阻害剤
JPH05201970A (ja) 1992-01-24 1993-08-10 Japan Tobacco Inc 新規プロリン誘導体
JP3318622B2 (ja) 1992-05-27 2002-08-26 独立行政法人産業技術総合研究所 プロリルエンドペプチダーゼ阻害剤
GB9212308D0 (en) 1992-06-10 1992-07-22 Ici Plc Therapeutic compositions
GB9213215D0 (en) 1992-06-20 1992-08-05 Wellcome Found Peptides
JPH06116284A (ja) 1992-10-02 1994-04-26 Yamanouchi Pharmaceut Co Ltd 新規ペプチド
PT664291E (pt) 1992-10-05 2000-11-30 Ube Industries Composto de pirimidina
US5260286A (en) 1992-10-16 1993-11-09 Japan Tobacco, Inc. 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists
CA2149892C (en) 1992-11-20 1998-12-08 Koji Kobayashi Compound having prolyl endopeptidase inhibitory activity and pharmaceutical use thereof
US5354758A (en) 1992-12-16 1994-10-11 Japan Tobacco Inc. Benzomorphans useful as NMDA receptor antagonists
JPH06192298A (ja) 1992-12-24 1994-07-12 Mitsui Toatsu Chem Inc 新規機能性ペプチド
DE4326465A1 (de) 1993-01-20 1995-02-09 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
WO1994017197A1 (fr) 1993-01-25 1994-08-04 Takeda Chemical Industries, Ltd. ANTICORPS DIRIGE CONTRE LE β-AMYLOIDE OU UN DERIVE DE CE DERNIER ET SON UTILISATION
JPH06234693A (ja) 1993-02-09 1994-08-23 Snow Brand Milk Prod Co Ltd 新規イソテトラセノン系物質及びその製造法
FR2701480B1 (fr) 1993-02-15 1995-05-24 Sanofi Elf Composés à groupe sulfamoyle et amidino, leur procédé de préparation et les compositions pharmaceutiques les contenant.
EP0611769A1 (en) 1993-02-16 1994-08-24 Merrell Dow Pharmaceuticals Inc. Silylated acetylcholinesterase inhibitors
WO1994020476A1 (fr) 1993-03-02 1994-09-15 Fujisawa Pharmaceutical Co., Ltd. Nouveau compose heterocyclique
FR2702150B1 (fr) 1993-03-03 1995-04-07 Rhone Poulenc Rorer Sa Application de dérivés de 2H-1,2-4-benzothiadiazine-3(4H)-one-1,1-dioxyde comme antagonistes non compétitifs du récepteur NMDA.
FR2703050B1 (fr) 1993-03-24 1995-04-28 Adir Nouveaux dérivés bicycliques azotés, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent.
EP0627400A1 (en) 1993-06-04 1994-12-07 Merrell Dow Pharmaceuticals Inc. Aromatic acetylcholinesterase inhibitors
CA2165200A1 (en) 1993-06-18 1995-01-05 Ambikaipakan Balasubramaniam Neuropeptide y antagonists and agonists
AU6983894A (en) 1993-06-30 1995-01-24 Zeria Pharmaceutical Co., Ltd. Thiazolidine derivative and medicine containing the same
FR2707643B1 (fr) 1993-07-16 1995-08-11 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]pyrazine-4-one, leur préparation et les médicaments les contenant.
FR2707645B1 (fr) 1993-07-16 1995-08-11 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]pirazine-4-one, leur préparation et les médicaments les contenant.
EP0709373B1 (en) 1993-07-23 2001-10-17 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Pyrrolidine derivative
FR2711993B1 (fr) 1993-11-05 1995-12-01 Rhone Poulenc Rorer Sa Médicaments contenant des dérivés de 7H-imidazol[1,2-a]pyrazine-8-one, les nouveaux composés et leur préparation.
EP0731788B1 (en) 1993-12-02 2002-09-11 Merrell Pharmaceuticals Inc. Prolyl endopeptidase inhibitors
FR2717805B1 (fr) 1994-03-28 1996-05-10 Rhone Poulenc Rorer Sa Dérivés de 5H-indeno[1,2-b]pyrazine-2,3-dione, leur préparation et les médicaments les contenant .
FR2717812B1 (fr) 1994-03-28 1996-05-10 Rhone Poulenc Rorer Sa Indeno[1,2-e]pyrazine-4-ones, leur préparation et les médicaments les contenant.
FR2717813B1 (fr) 1994-03-28 1996-05-10 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, leur préparation et les médicaments les contenant .
FR2717811B1 (fr) 1994-03-28 1996-04-26 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]pyrazine-4-one, leur préparation et les médicaments les contenant.
JPH07267988A (ja) 1994-03-31 1995-10-17 Yamanouchi Pharmaceut Co Ltd 新規ペプチド
GB9410320D0 (en) 1994-05-24 1994-07-13 Fisons Corp Novel therapeutic method
GB9418443D0 (en) 1994-09-13 1994-11-02 Pfizer Ltd Therapeutic agents
IL115613A0 (en) 1994-10-20 1996-01-19 Lilly Co Eli Bicyclic neuropeptide y receptor antagonists
US5663192A (en) 1994-10-20 1997-09-02 Eli Lilly And Company Heterocyclic neuropeptide Y receptor antagonists
US6562862B1 (en) 1994-10-20 2003-05-13 Eli Lilly And Company Methods of inhibiting physiological conditions associated with an excess of neuropeptide Y
FR2726275B1 (fr) 1994-11-02 1996-12-06 Rhone Poulenc Rorer Sa Spiro heterocycle-imidazo(1,2-a)indeno(1,2-e)pyrazine)-4'- ones, leur preparation et les medicaments les contenants
IL116584A0 (en) 1994-12-29 1996-03-31 Res Dev Foundation Novel flavin adenine dinucleotide analogue inhibitors of monoamine oxidase
US5691368A (en) 1995-01-11 1997-11-25 Hoechst Marion Roussel, Inc. Substituted oxazolidine calpain and/or cathepsin B inhibitors
GB9500601D0 (en) 1995-01-12 1995-03-01 Wellcome Found Modified peptides
US5786180A (en) 1995-02-14 1998-07-28 Bayer Corporation Monoclonal antibody 369.2B specific for β A4 peptide
US5552411A (en) 1995-05-26 1996-09-03 Warner-Lambert Company Sulfonylquinolines as central nervous system and cardiovascular agents
US5635503A (en) 1995-06-07 1997-06-03 Bristol-Myers Squibb Company Dihydropyridine npy antagonists: piperazine derivatives
US5554621A (en) 1995-06-07 1996-09-10 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists: nitrogen heterocyclic derivatives
IL117997A0 (en) 1995-06-07 1996-10-31 Pfizer Neuropeptide Y1 specific ligands
US5668151A (en) 1995-06-07 1997-09-16 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists: piperidine derivatives
JP3727383B2 (ja) 1995-07-31 2005-12-14 月桂冠株式会社 プロリルエンドペプチダーゼ阻害剤
AU717422B2 (en) 1995-09-01 2000-03-23 Eli Lilly And Company Indolyl neuropeptide Y receptor antagonists
WO1997012613A1 (en) 1995-10-05 1997-04-10 Warner-Lambert Company Method for treating and preventing inflammation and atherosclerosis
ES2100129B1 (es) 1995-10-11 1998-02-16 Medichem Sa Nuevos compuestos aminopiridinicos policiclicos inhibidores de acetilcolinesterasa, procedimiento para su preparacion y su utilizacion.
DE19544685A1 (de) 1995-11-30 1997-06-05 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE19544687A1 (de) 1995-11-30 1997-06-05 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE19544686A1 (de) 1995-11-30 1997-06-05 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
AU7692896A (en) 1995-12-01 1997-06-27 Novartis Ag Quinazolin-2,4-diazirines as NPY receptor antagonist
WO1997019682A1 (en) 1995-12-01 1997-06-05 Synaptic Pharmaceutical Corporation Aryl sulfonamide and sulfamide derivatives and uses thereof
WO1997020821A1 (en) 1995-12-01 1997-06-12 Novartis Ag Heteroaryl derivatives
WO1997020823A2 (en) 1995-12-01 1997-06-12 Novartis Ag 2-amino quinazoline derivatives as npy receptor antagonists
WO1997020820A1 (en) 1995-12-01 1997-06-12 Novartis Ag Heteroaryl compounds
JPH09157253A (ja) 1995-12-12 1997-06-17 Yamanouchi Pharmaceut Co Ltd 新規アミノ酸誘導体
ZA9610736B (en) 1995-12-22 1997-06-27 Warner Lambert Co 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists
ZA9610741B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists
ZA9610745B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists
CA2242579A1 (en) 1996-01-09 1997-07-17 Eli Lilly And Company Benzimidzolyl neuropeptide y receptor antagonists
GB9605027D0 (en) 1996-03-09 1996-05-08 Pfizer Ltd Quinoxalinediones
US5662723A (en) 1996-03-22 1997-09-02 Libbey Glass Inc. Apparatus and method for forming a decorative pattern on glassware having an edge
PT892796E (pt) 1996-04-12 2002-03-28 Aventis Pharma Inc Derivados de isatina como inibidores de acetilcolinesterase e analgesicos
WO1997046250A1 (en) 1996-06-04 1997-12-11 Synaptic Pharmaceutical Corporation Methods of modifying feeding behavior, compounds useful in such methods, and dna encoding a hypothalamic atypical neuropeptide y/peptide yy receptor (y5)
ES2184111T3 (es) 1996-07-05 2003-04-01 Wwk Trust Composiciones para el tratamiento de neuropatias perifericas que contienen antidepresivos y/o inhibidores de la monoaminoxidasa y/o vitamina b12 y/o precursores o inductores de un neurotransmisor.
DK0918761T3 (da) 1996-07-23 2003-08-25 Neurogen Corp Visse amido- og aminosubstituerede benzylaminderivater, en ny klasse af neuropeptid Y1-specifikke ligander
EP0915860A1 (en) 1996-07-23 1999-05-19 Neurogen Corporation Certain substituted benzylamine derivatives; a new class of neuropeptide-y1 specific ligands
EP0915859B1 (en) 1996-07-23 2003-01-02 Neurogen Corporation Certain substituted benzylamine derivatives; a new class of neuropeptide y1 specific ligands
WO1998005337A1 (en) 1996-08-01 1998-02-12 Cocensys, Inc. Use of gaba and nmda receptor ligands for the treatment of migraine headache
JP2000516611A (ja) 1996-08-14 2000-12-12 ワーナー―ランバート・コンパニー Ｍｃｐ―１アンタゴニストとしての２―フェニルベンズイミダゾール誘導体
PT984778E (pt) 1996-08-23 2002-09-30 Agouron Pharma Ligandos do neuropeptido y
JP3880664B2 (ja) 1996-09-04 2007-02-14 月桂冠株式会社 プロリルエンドペプチダーゼ阻害ペプチド
WO1998010757A2 (en) 1996-09-11 1998-03-19 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services The use of functional n-methyl-d-aspartate antagonists to ameliorate or prevent aminoglycoside-induced ototoxicity
WO1998015647A1 (en) 1996-10-08 1998-04-16 Novartis Ag Modulation of apoptosis
FR2754709B1 (fr) 1996-10-23 1999-03-05 Sanofi Sa Composition cosmetique contenant un antagoniste des recepteurs du neuropeptide gamma et alpha 2 antagonistes susceptibles d'etre incorpores dans une telle composition
AU5716898A (en) 1997-01-08 1998-08-03 Warner-Lambert Company Acetylcholinesterase inhibitors in combination with muscarinic agonists for the treatment of alzheimer's disease
US20030068316A1 (en) 1997-02-05 2003-04-10 Klein William L. Anti-ADDL antibodies and uses thereof
JP2894445B2 (ja) 1997-02-12 1999-05-24 日本たばこ産業株式会社 Ｃｅｔｐ活性阻害剤として有効な化合物
CA2284001A1 (en) 1997-03-13 1998-09-17 Keith Tipton Cytoprotective agents comprising monoamine oxidase inhibitors
NZ337765A (en) 1997-04-09 2001-09-28 Mindset Biopharmaceuticals Usa Recombinant antibodies having specificity for beta-amyloid N-terminus and C-terminus and use in treating Alzheimer's Disease
US8173127B2 (en) 1997-04-09 2012-05-08 Intellect Neurosciences, Inc. Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof
WO1998046559A1 (en) 1997-04-16 1998-10-22 Arqule, Inc. SYNTHESIS AND USE OF α-KETOAMIDE DERIVATIVES AND ARRAYS
EP0980247A1 (en) 1997-05-07 2000-02-23 Algos Pharmaceutical Corporation Composition and method combining an antidepressant with an nmda receptor antagonist, for treating neuropathic pain
WO1998050075A1 (en) 1997-05-07 1998-11-12 Algos Pharmaceutical Corporation Cox-2 inhibitors in combination with nmda-blockers for treating pain
JP3255080B2 (ja) 1997-05-28 2002-02-12 日新電機株式会社 ガス絶縁開閉装置
JP3963488B2 (ja) 1997-06-30 2007-08-22 メルツ ファーマ ゲゼルシャフト ミット ベシュレンクテル ハフツンク ウント コンパニー コマンディゲゼルシャフト アウフ アクチェン １−アミノ−アルキルシクロヘキサンｎｍｄａ受容体拮抗薬
GB9716657D0 (en) 1997-08-07 1997-10-15 Zeneca Ltd Chemical compounds
GB9716879D0 (en) 1997-08-08 1997-10-15 Shire Int Licensing Bv Treatment of attention deficit disorders
WO1999007413A1 (en) 1997-08-11 1999-02-18 Algos Pharmaceutical Corporation Substance p inhibitors in combination with nmda-blockers for treating pain
SE9703376D0 (sv) 1997-09-18 1997-09-18 Astra Ab A new combination
SE9703414D0 (sv) 1997-09-23 1997-09-23 Astra Ab New compounds
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US7179892B2 (en) 2000-12-06 2007-02-20 Neuralab Limited Humanized antibodies that recognize beta amyloid peptide
TWI239847B (en) 1997-12-02 2005-09-21 Elan Pharm Inc N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease
AU3034299A (en) 1998-03-09 1999-09-27 Fondatech Benelux N.V. Serine peptidase modulators
US6007841A (en) 1998-03-13 1999-12-28 Algos Pharmaceutical Corporation Analgesic composition and method for treating pain
GB9805561D0 (en) 1998-03-16 1998-05-13 Merck Sharp & Dohme A combination of therapeutic agents
US6541208B1 (en) 1998-03-17 2003-04-01 University Of Maryland Biotechnology Institute Diagnostic method for distinguishing HIV-associated dementia from other forms of dementia
DE19812331A1 (de) 1998-03-20 1999-09-23 Merck Patent Gmbh Piperidinderivate
US6054451A (en) 1998-04-21 2000-04-25 Algos Pharmaceutical Corporation Analgesic composition and method for alleviating pain
WO1999057120A1 (en) 1998-05-04 1999-11-11 Neotherapeutics, Inc. Novel serotonin-like 9-substituted hypoxanthine and methods of use
AU3879899A (en) 1998-05-04 1999-11-23 Neotherapeutics, Inc. Novel dopamine-like 9-substituted hypoxanthine and methods of use
DK1078005T3 (da) 1998-05-21 2010-08-09 Univ Tennessee Res Foundation Fremgangsmåder til amyloidfjernelse ved anvendelse af anti-amyloidantistoffer
DE69941260D1 (de) 1998-06-24 2009-09-24 Aventis Pharma Inc Fluorphenyl-harzverbindungen
DE19828113A1 (de) 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV
DE19828114A1 (de) 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV
PE20000728A1 (es) 1998-06-26 2000-08-21 Cocensys Inc Heterociclos 4-bencil piperidina alquilsulfoxido y su uso como antagonistas receptores subtipo-selectivo nmda
US6262081B1 (en) 1998-07-10 2001-07-17 Dupont Pharmaceuticals Company Composition for and method of treating neurological disorders
US6218383B1 (en) 1998-08-07 2001-04-17 Targacept, Inc. Pharmaceutical compositions for the prevention and treatment of central nervous system disorders
IL125809A (en) 1998-08-17 2005-08-31 Finetech Lab Ltd Process and intermediates for production of donepezil and related compounds
JP4208299B2 (ja) 1998-08-19 2009-01-14 東レ株式会社 金属板貼合わせ成形加工用ポリエステルフィルム
IT1304904B1 (it) 1998-09-11 2001-04-05 Eisai Co Ltd Derivati anticolinesterasici per il trattamento delle sindromidolorose funzionali e/o organiche
JP2002527469A (ja) 1998-10-16 2002-08-27 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 認識を改良するための療法
AU1408699A (en) 1998-11-12 2000-06-05 Algos Pharmaceutical Corporation Cox-2 inhibitors in combination with nmda-blockers for treating pain
AU1738800A (en) 1998-11-23 2000-06-13 Bonnie Davis Dosage formulations for acetylcholinesterase inhibitors
WO2000030674A1 (en) 1998-11-26 2000-06-02 Ferring Bv Neuropeptide y y4 agents in the treatment of reproductive disorders
DE69927705T2 (de) 1998-12-11 2006-07-20 Bonnie M. Davis Verwendung von acetylcholinesterase inhibitoren zur modulierung der hypothalamus-hypophysen-gonadenachse
GB9902453D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902461D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902459D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902455D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902452D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
WO2000056711A1 (en) 1999-03-23 2000-09-28 Sumitomo Pharmaceuticals Co., Ltd. Tricyclic indole-2-carboxylic acid compound used as nmda receptor antagonist
CA2363984A1 (en) 1999-04-15 2000-10-26 Merck Frosst Canada & Co. Antibodies that recognize app cleaved by caspases and methods of use
US6121311A (en) 1999-04-28 2000-09-19 Japan Tobacco Inc. Method for treating cocainism
MXPA01011321A (es) 1999-05-05 2003-08-01 Johnson & Johnson Neuropeptidos y ligandos de receptores 3a, 4, 5, 9b-tetrahidro-1h-benz(e)indol-2-il amino derivados utiles en el tratamiento de obesidad y otros trastornos.
JP3148739B2 (ja) 1999-05-19 2001-03-26 ドーマー株式会社 プロリルエンドペプチダーゼ阻害剤
WO2000077178A1 (en) 1999-06-16 2000-12-21 Boston Biomedical Research Institute IMMUNOLOGICAL CONTROL OF β-AMYLOID LEVELS IN VIVO
WO2001000215A1 (en) 1999-06-25 2001-01-04 Wake Forest University Compositions for treating or preventing neurodegeneration and cognitive decline
US6316449B1 (en) 1999-07-08 2001-11-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists
DE19936521A1 (de) 1999-08-06 2001-02-15 Gruenenthal Gmbh Substituierte Pyrrolidin-2,3,4-trion-3-oxim-Derivate
DE19936719A1 (de) 1999-08-06 2001-02-15 Gruenenthal Gmbh Substituierte 1,5-Dihydropyrrol-2-on-Derivate
JP2003507013A (ja) 1999-08-13 2003-02-25 ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク βシートフィブリルのＲＡＧＥへの結合を阻害する方法及びその結果
EP1078632A1 (en) 1999-08-16 2001-02-28 Sanofi-Synthelabo Use of monoamine oxydase inhibitors for the manufacture of drugs intended for the treatment of obesity
TWI283577B (en) 1999-10-11 2007-07-11 Sod Conseils Rech Applic Pharmaceutical composition of imidazole derivatives acting as modulators of sodium channels and the use thereof
UA72558C2 (uk) 1999-11-01 2005-03-15 Мерц Фарма Гмбх Унд Ко. Кгаа 1-аміноалкілциклогексанові антагоністи рецептора nmda
AU779875B2 (en) 2000-01-24 2005-02-17 Merck Sharp & Dohme Limited Gamma-secretase inhibitors
CA2399080C (en) 2000-02-03 2013-05-21 Millennium Pharmaceuticals, Inc. Humanized anti-ccr2 antibodies and methods of use therefor
SI1257584T2 (sl) 2000-02-24 2013-07-31 Washington University St. Louis Humanizirana protitelesa, ki veĹľejo amiloidni peptid beta
GB0005251D0 (en) 2000-03-03 2000-04-26 Merck Sharp & Dohme Therapeutic compounds
US20030144255A1 (en) 2000-03-06 2003-07-31 Bain Allen I Compositions for prevention and treatment of dementia
US6992081B2 (en) 2000-03-23 2006-01-31 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
JP2003528071A (ja) 2000-03-23 2003-09-24 エラン ファーマスーティカルズ インコーポレイテッド アルツハイマー病治療用組成物および方法
GB0008710D0 (en) 2000-04-07 2000-05-31 Merck Sharp & Dohme Therapeutic compounds
US6706741B2 (en) 2000-04-13 2004-03-16 Eisai Co., Ltd. Acetylcholinesterase inhibitors containing 1-benzyl-pyridinium salts
ATE337292T1 (de) 2000-04-26 2006-09-15 Warner Lambert Co Trans-n- 4-(4-hydroxyphenyl)cyclohexylö-3- phenylpropionamid als subtyp-selektiver nmda rezeptor antagonist
US20010036949A1 (en) 2000-05-09 2001-11-01 Coe Jotham Wadsworth Pharmaceutical composition and method of treatment of diseases of cognitive dysfunction in a mammal
CA2410660A1 (en) 2000-06-01 2001-12-06 Warner-Lambert Company Cyclohexylamine derivatives as subtype selective nmda receptor antagonists
MXPA02010503A (es) 2000-06-06 2003-03-10 Warner Lambert Co Ciclohexilaminas biciclicas y su uso como antagonistas del receptor nmda.
EP1299374B1 (en) 2000-06-22 2006-12-27 Pharmos Corporation Novel non-psychotropic cannabinoids
GB0015488D0 (en) 2000-06-23 2000-08-16 Merck Sharp & Dohme Therapeutic agents
US6713276B2 (en) 2000-06-28 2004-03-30 Scios, Inc. Modulation of Aβ levels by β-secretase BACE2
ATE302751T1 (de) 2000-06-30 2005-09-15 Elan Pharm Inc Verbindungen zur behandlung der alzheimerischen krankheit
US6686449B2 (en) 2000-06-30 2004-02-03 Pharmacia & Upjohn Company Mutant presenilin 1 polypeptides
GB0016681D0 (en) 2000-07-06 2000-08-23 Merck Sharp & Dohme Therapeutic compounds
US6556971B1 (en) 2000-09-01 2003-04-29 Snap-On Technologies, Inc. Computer-implemented speech recognition system training
WO2002027418A2 (en) 2000-09-25 2002-04-04 Motorwiz, Inc. Model-based machine diagnostics and prognostics using theory of noise and communications
US20020151591A1 (en) 2000-10-17 2002-10-17 Anabella Villalobos Combination use of acetylcholinesterase inhibitors and GABAa inverse agonists for the treatment of cognitive disorders
HU227197B1 (en) 2000-10-24 2010-10-28 Richter Gedeon Nyrt Nmda receptor antagonist carboxylic acid amide derivatives and pharmaceutical compositions containing them
AU1074702A (en) 2000-11-02 2002-05-15 Merck Sharp & Dohme Sulfamides as gamma-secretase inhibitors
US20020150948A1 (en) 2000-11-03 2002-10-17 Gerardo Castillo Antibody PTI-HS7 for treatment of alzheimer's disease and other amyloidoses and parkinson's disease
TWI255272B (en) 2000-12-06 2006-05-21 Guriq Basi Humanized antibodies that recognize beta amyloid peptide
US6495335B2 (en) 2000-12-07 2002-12-17 Mario Chojkier Compositions and methods for diagnosing alzheimer's disease
US6670364B2 (en) 2001-01-31 2003-12-30 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
TWI245761B (en) 2001-03-01 2005-12-21 Telik Inc Antagonists of MCP-1 function and methods of use thereof
JP2005506292A (ja) 2001-03-08 2005-03-03 エモリー　ユニバーシティ ｐＨに依存するＮＭＤＡレセプターアンタゴニスト
US6649196B2 (en) 2001-03-12 2003-11-18 Mayo Foundation For Medical Education And Research Methods of reducing β-amyloid polypeptides
US6815175B2 (en) 2001-03-16 2004-11-09 Cornell Research Foundation, Inc. Anti-amyloid peptide antibody based diagnosis and treatment of a neurological disease or disorder
TWI236474B (en) 2001-04-03 2005-07-21 Telik Inc Antagonists of MCP-1 function and methods of use thereof
ES2437875T3 (es) 2001-04-30 2014-01-14 Eli Lilly And Company Anticuerpos humanizados que reconocen el péptido beta-amiloide
AU2002257162A1 (en) 2001-04-30 2002-11-11 Eli Lilly And Company Humanized antibodies
SI20922A (sl) 2001-05-18 2002-12-31 Krka Tovarna Zdravil, D.D., Novo Mesto Monoklonsko protitelo, ki nevtralizira aktivnost katepsina B, in njegove uporabe
US6562783B2 (en) 2001-05-30 2003-05-13 Neurologic, Inc. Phosphinylmethyl and phosphorylmethyl succinic and glutauric acid analogs as β-secretase inhibitors
MXPA03011046A (es) 2001-06-01 2004-06-25 Elan Pharm Inc Hidroxialquilaminas.
MXPA04000140A (es) 2001-06-27 2004-06-03 Elan Pharm Inc Derivados de beta-hidroxiamina utiles en el tratamiento de enfermedad de alzheimer.
MXPA04000737A (es) 2001-07-24 2004-07-08 Richter Gedeon Vegyeszet Derivados de piperidina como antagonistas receptores de nmda.
WO2003012141A1 (en) 2001-07-31 2003-02-13 Takeda Chemical Industries, Ltd. Method of screening alzheimer’s disease-associated gene
BR0211698A (pt) 2001-08-03 2004-11-09 Schering Corp Inibidores de gama-secretase
EP1420032B2 (en) 2001-08-03 2015-12-16 Medical & Biological Laboratories Co., Ltd. Antibody recognizing gm1 ganglioside-bound amyloid beta-protein and dna encoding the antibody
WO2003013527A1 (en) 2001-08-03 2003-02-20 Schering Corporation Sulfonamide derivatives as gamma secretase inhibitors
US20040192898A1 (en) 2001-08-17 2004-09-30 Jia Audrey Yunhua Anti-abeta antibodies
AU2002324468A1 (en) 2001-08-17 2003-03-03 Eli Lilly And Company Rapid improvement of cognition in conditions related to abeta
EP1423127A1 (en) 2001-08-30 2004-06-02 Ortho-Mcneil Pharmaceutical, Inc. Treatment of dementia and memory disorders with anticonvulsants and acetylcholinesterase inhibitors
EP1448218A4 (en) 2001-10-23 2009-01-14 Oklahoma Med Res Found BETA SECRETASE INHIBITORS AND METHODS OF USE
CN100488982C (zh) 2001-11-02 2009-05-20 迪尔基因国际有限公司 与β-淀粉样蛋白结合并引起蛋白质构象转变的单克隆抗体的制备方法
EP1447095B1 (en) 2001-11-02 2012-06-13 Kensuke Egashira Preventives and/or remedies for post-transplant arteriosclerosis as rejection of organ transplant
WO2003040183A2 (en) 2001-11-09 2003-05-15 The Genetics Company, Inc Compounds for the diagnosis/prevention/treatment of alzheimer's disease
RS54204A (sr) 2001-11-19 2006-12-15 Elan Pharmaceuticals Inc. 3,4-disupstituisani, 3,5-disupstituisani i 3,4,5- supstituisani piperidini i piperazini
EP1572894B1 (en) 2001-11-21 2016-04-13 New York University Synthetic immunogenic but non-deposit-forming polypeptides and peptides homologous to amyloid beta, prion protein, amylin, alpha synuclein, or polyglutamine repeats for induction of an immune response thereto
AU2002354433A1 (en) 2001-12-06 2003-06-17 Japan As Represented By Secretary Of Chubu National Hospital Alzheimer's disease-associated gene and protein and use thereof
WO2003051374A2 (en) 2001-12-17 2003-06-26 New York State Office Of Mental Health SEQUESTRATION OF Aβ IN THE PERIPHERY IN THE ABSENCE OF IMMUNOMODULATING AGENT AS A THERAPEUTIC APPROACH FOR THE TREATMENT OR PREVENTION OF BETA-AMYLOID RELATED DISEASES
BR0215240A (pt) 2001-12-19 2004-10-26 Atherogenics Inc Derivados de calcona e seu uso no tratamento de doenças
AU2002357359B2 (en) 2001-12-21 2009-01-08 Csl Limited Compositions comprising immunoreactive reagents and saponins, and methods of use thereof
AU2003235799A1 (en) 2002-01-08 2003-07-24 Nordic Bioscience A/S Modulation of iamt (pimt or pcmt) in immune system
CA2473441A1 (en) 2002-01-18 2003-07-24 The Genetics Company Inc. Beta-secretase inhibitors
US20070021345A1 (en) 2003-06-30 2007-01-25 Ehud Gazit Peptides antibodies directed thereagainst and methods using same for diagnosing and treating amyloid-associated diseases
KR20040081165A (ko) 2002-01-31 2004-09-20 텔 아비브 유니버시티 퓨쳐 테크놀로지 디벨롭먼트 엘.피. 펩타이드 항체 및 이를 이용한 아밀로이드-관련 질환의진단 및 치료 방법
US20040171614A1 (en) 2002-02-06 2004-09-02 Schering-Plough Corporation Novel gamma secretase inhibitors
TW200302717A (en) 2002-02-06 2003-08-16 Schering Corp Novel gamma secretase inhibitors
AR038568A1 (es) 2002-02-20 2005-01-19 Hoffmann La Roche Anticuerpos anti-a beta y su uso
MY139983A (en) 2002-03-12 2009-11-30 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
JP4405811B2 (ja) 2002-03-29 2010-01-27 エーザイ・アール・アンド・ディー・マネジメント株式会社 （１−インダノン）−（１，２，３，６−テトラヒドロピリジン）誘導体
AU2003226356A1 (en) 2002-04-12 2003-10-27 Ramot At Tel Aviv University Ltd. Prevention of brain inflammation as a result of induced autoimmune response
JP4662719B2 (ja) 2002-04-19 2011-03-30 ザ ガバニング カウンシル オブ ザ ユニバーシティ オブ トロント アルツハイマー病の処置のための免疫学的方法および組成物
JP4404643B2 (ja) 2002-04-24 2010-01-27 啓 森 ガンマセクレターゼ阻害剤
CN1649845A (zh) 2002-04-26 2005-08-03 先灵公司 蝇蕈碱拮抗剂
US7205336B2 (en) 2002-05-17 2007-04-17 Merck & Co., Inc. β-secretase inhibitors
AU2003227516B2 (en) 2002-05-31 2008-03-20 H. Lundbeck A/S A combination of an NMDA-antagonist and acetylcholine esterase inhibitors for the treatment of alzheimer's disease
ATE357487T1 (de) 2002-06-19 2007-04-15 Cytec Surface Specialties Sa Halb-glänzende pulverbeschichtungszusammensetzungen
EP1523309A2 (en) 2002-07-19 2005-04-20 Khalid Iqbal Nmda receptor antagonists and their use in inhibiting abnormal hyperphosphorylation of microtubule associated protein tau
US7557137B2 (en) 2002-08-05 2009-07-07 Bristol-Myers Squibb Company Gamma-lactams as beta-secretase inhibitors
ES2201929B1 (es) 2002-09-12 2005-05-16 Araclon Biotech, S.L. Anticuerpos policlonales, metodo de preparacion y uso de los mismos.
US8871447B2 (en) 2002-09-12 2014-10-28 The Regents Of The University Of California Immunogens and corresponding antibodies specific for high molecular weight aggregation intermediates common to amyloids formed from proteins of differing sequence
JP4426449B2 (ja) 2002-09-12 2010-03-03 財団法人化学及血清療法研究所 ヒト抗ヒトｍｃｐ−１抗体及び該抗体フラグメント
AU2003282804A1 (en) 2002-09-20 2004-04-08 Axys Pharmaceuticals, Inc. 3-(3,5-disubstituted-4-hydroxyphenyl)propionamide derivatives as cathepsin b inhibitors
US7273889B2 (en) 2002-09-25 2007-09-25 Innovative Drug Delivery Systems, Inc. NMDA receptor antagonist formulation with reduced neurotoxicity
WO2004029629A1 (en) 2002-09-27 2004-04-08 Janssen Pharmaceutica N.V. N-11 truncated amyloid-beta nomoclonal antibodies, compositions, methods and uses
WO2004031400A2 (en) 2002-10-01 2004-04-15 Northwestern University Amyloid beta-derived diffusible ligands (addls), addl-surrogates, addl-binding molecules, and uses thereof
GB0223038D0 (en) 2002-10-04 2002-11-13 Merck Sharp & Dohme Therapeutic compounds
GB0223039D0 (en) 2002-10-04 2002-11-13 Merck Sharp & Dohme Therapeutic compounds
GB0223494D0 (en) 2002-10-09 2002-11-13 Neuropharma Sa Dual binding site acetylcholinesterase inhibitors for the treatment of alzheimer's disease
BR0315157A (pt) 2002-10-09 2005-08-09 Rinat Neuroscience Corp Métodos de tratar doença de alzheimer empregando-se anticorpos direcionados contra peptìdeo beta amilóide e composições deste
AU2003274353B2 (en) 2002-10-24 2007-04-05 Merz Pharma Gmbh & Co. Kgaa Combination therapy using 1-aminocyclohexane derivatives and acetylcholinesterase inhibitors
US20040082543A1 (en) 2002-10-29 2004-04-29 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
AU2003285296A1 (en) 2002-10-30 2004-05-25 Nordic Bioscience A/S Coumpounds modulating the activity of gapdh and/or iamt
GB0225474D0 (en) 2002-11-01 2002-12-11 Merck Sharp & Dohme Therapeutic agents
FR2846667B1 (fr) 2002-11-06 2004-12-31 Pasteur Institut Fragments variables d'anticorps de camelides a chaine unique diriges contre le peptide beta-amyloide 1-42 et leurs applications pour le diagnostic et le traitement des maladies neuroagregatives
ATE443043T1 (de) 2002-11-12 2009-10-15 Merck & Co Inc Phenylcarboxamide als beta-sekretase-hemmer zur behandlung von alzheimer
WO2004056727A2 (en) 2002-12-19 2004-07-08 Atherogenics, Inc. Process of making chalcone derivatives
CA2512111A1 (en) 2003-01-07 2004-07-29 Merck And Co., Inc. Macrocyclic beta-secretase inhibitors for treatment of alzheimer's disease
DE10303974A1 (de) 2003-01-31 2004-08-05 Abbott Gmbh & Co. Kg Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung
PL378571A1 (pl) 2003-02-01 2006-05-02 Neuralab Limited Czynna immunizacja dla wytworzenia przeciwciał przeciw rozpuszczalnemu A-ß
PL378405A1 (pl) 2003-02-04 2006-04-03 F. Hoffmann-La Roche Ag Pochodne malonoamidu jako inhibitory <$Egamma> - sekretazy
WO2004071408A2 (en) 2003-02-10 2004-08-26 Applied Molecular Evolution, Inc. Aβ BINDING MOLECULES
CN1777436A (zh) 2003-02-18 2006-05-24 罗斯坎普研究有限责任公司 β和γ分泌酶抑制剂的抗血管生成和抗肿瘤性
US8663650B2 (en) 2003-02-21 2014-03-04 Ac Immune Sa Methods and compositions comprising supramolecular constructs
EP1454627A1 (en) 2003-03-06 2004-09-08 MyoContract Ltd. Alpha-Keto carbonyl calpain inhibitors
WO2004084830A2 (en) 2003-03-21 2004-10-07 Buck Institute Method for treating alzheimer’s dementia
US20040191334A1 (en) 2003-03-24 2004-09-30 Pang-Chui Shaw Use of transhinone derivates as cholinesterase inhibitors in treating related diseases
CA2520125A1 (en) 2003-03-28 2004-10-14 Acadia Pharmaceuticals Inc. Muscarinic m1 receptor agonists for pain management
KR20060054174A (ko) 2003-03-28 2006-05-22 센토코 인코포레이티드 항-아밀로이드 항체, 조성물, 방법 및 용도
EP1611144B1 (en) 2003-04-09 2010-09-15 Wyeth LLC Derivatives of 2-(8,9-dioxo-2,6-diazabicyclo(5.2.0)non-1(7)-en-2-yl)alkyl phosphonic acid and their use as n-methyl-d-aspartate (nmda) recetor antagonists
GB0308382D0 (en) 2003-04-10 2003-05-21 Univ Cambridge Tech Therapeutic methods and means
GB0308318D0 (en) 2003-04-10 2003-05-14 Merck Sharp & Dohme Therapeutic agents
WO2004099134A2 (en) * 2003-05-05 2004-11-18 Prosidion Ltd. Glutaminyl based dp iv-inhibitors
CN1784220B (zh) 2003-05-05 2011-08-03 前体生物药物股份公司 谷氨酰胺酰基和谷氨酸环化酶效应物的应用
ZA200508439B (en) * 2003-05-05 2007-03-28 Probiodrug Ag Medical use of inhibitors of glutaminyl and glutamate cyclases
ES2246178B1 (es) 2003-05-08 2007-03-01 Universidad De Zaragoza. Uso de anticuerpos para el tratamiento de enfermedades amiloideas.
WO2004101562A2 (en) 2003-05-13 2004-11-25 Schering Corporation Bridged n-arylsulfonylpiperidines as gamma-secretase inhibitors
EP1644346A1 (en) 2003-05-16 2006-04-12 MERCK SHARP &amp; DOHME LTD. Cyclic sulfonamides for inhibition of gamma-secretase
EA010430B1 (ru) 2003-05-27 2008-08-29 Форест Лэборэтериз, Инк. Сочетание антагониста nmda-рецептора и селективного ингибитора обратного захвата серотонина для лечения депрессии и других психических расстройств
TWI374893B (en) 2003-05-30 2012-10-21 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
AU2004255183A1 (en) 2003-06-30 2005-01-20 Merck & Co., Inc. N-alkyl phenylcarboxamide beta-secretase inhibitors for the treatment of Alzheimer's disease
CN1909897A (zh) 2003-07-01 2007-02-07 默克公司 用于治疗阿尔茨海默病的苯基羧化物β－分泌酶抑制剂
WO2005007614A1 (en) 2003-07-03 2005-01-27 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services 6011 Monoamine oxidase inhibitors
DE602004027048D1 (de) 2003-07-16 2010-06-17 Resverlogix Inc Verbindungen und methoden für das downregulating der effekte von tgf-beta
EP1671129A1 (en) 2003-07-21 2006-06-21 Angiogenetics Sweden AB Compounds and methods for promoting angiogenesis by using a gamma-secretase inhibitor or inhibiting the gamma-secretase pathway
CA2529674A1 (en) 2003-07-28 2005-02-03 Merz Pharma Gmbh & Co. Kgaa The use of 1-amino-alkylcyclohexane compounds in the treatment of pain hypersensitivity
WO2005011599A2 (en) 2003-08-01 2005-02-10 Northwestern University Antibodies specific for toxic amyloid beta protein oligomers
GB0318447D0 (en) 2003-08-05 2003-09-10 Merck Sharp & Dohme Therapeutic agents
JP2007502278A (ja) 2003-08-14 2007-02-08 メルク　エンド　カムパニー　インコーポレーテッド アルツハイマー病の治療のための大員環β−セクレターゼ阻害剤
WO2005018424A2 (en) 2003-08-18 2005-03-03 Research Foundation For Mental Hygiene, Inc. Antibodies specific for fibrillar amyloid and a procedure to detect fibrillar amyloid deposits
WO2005023858A1 (en) 2003-09-05 2005-03-17 Cellzome Ag Protein complexes associated with app-processing
CA2538220A1 (en) 2003-09-09 2005-03-24 Takeda Pharmaceutical Company Limited Use of antibody
JP2007527865A (ja) 2003-09-12 2007-10-04 ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア 種々の配列を有するタンパク質から形成されたアミロイドに共通の高分子量凝集中間体に特異的なモノクローナル抗体
GB0322140D0 (en) 2003-09-22 2003-10-22 Pfizer Ltd Combinations
EP1667984B1 (en) 2003-09-24 2011-05-18 Merck Sharp & Dohme Ltd. Gamma-secretase inhibitors
ATE396973T1 (de) 2003-10-03 2008-06-15 Merck & Co Inc Benzylether- und benzylamino-beta-sekretase- hemmer zur behandlung von alzheimer-krankheit
PL1673347T3 (pl) 2003-10-06 2016-01-29 Hoffmann La Roche Podstawione pochodne dibenzo-azepiny i benzo-diazepiny użyteczne jako inhibitory gamma-sekretazy
WO2005035522A1 (en) 2003-10-08 2005-04-21 Pfizer Japan, Inc. 1-‘2-(4-hydroxyphenyl)-2-hydroxyethyl!-piperidin-4-ol compounds as nmda receptor antagonists
CN102302781A (zh) * 2003-10-15 2012-01-04 前体生物药物股份公司 谷氨酰胺酰基环化酶效应物和谷氨酸环化酶效应物的应用
MXPA06003762A (es) 2003-10-16 2006-06-14 Boehringer Ingelheim Int Composicion farmaceutica que comprende un inhibidor de recaptacion de neurotransmisor monoamina y un inhibidor de acetilcolinesterasa.
ATE411015T1 (de) 2003-10-22 2008-10-15 Merz Pharma Gmbh & Co Kgaa Verwendung von 1-aminocyclohexan-derivaten zur modifizierung der abscheidung von fibrillogenen as peptiden in amyloidpathien
WO2006058720A2 (en) 2003-11-03 2006-06-08 Probiodrug Ag Novel compounds for the treatment of neurological disorders
CA2544203A1 (en) 2003-11-11 2005-05-19 F. Hoffmann-La Roche Ag Phosphinic acids derivatives, beta-secretase inhibitors for the treatment of alzheimer's disease
JP4576386B2 (ja) 2003-11-24 2010-11-04 メルク・シャープ・エンド・ドーム・コーポレイション アルツハイマー病治療用のベンジルエーテルおよびベンジルアミノ系β−セクレターゼ阻害薬
UY28650A1 (es) 2003-12-05 2005-02-28 Forest Laboratories Memantina para la prevencion o disminucion de la conducta suicida y para el tratamiento de la depresion mayor asociada con esta conducta
EP1697308B1 (en) 2003-12-19 2014-03-19 Merck Sharp & Dohme Corp. Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease
AU2005205882A1 (en) 2004-01-22 2005-08-04 Neurosearch A/S Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and an N-methyl-D-aspartate (NMDA) receptors antagonist
CA2554959A1 (en) 2004-01-29 2005-08-11 Neuromolecular, Inc. Combination of a nmda receptor antagonist and a mao-inhibitor or a gadpf-inhibitor for the treatment of central nervous system-related conditions
EP1713780B1 (en) * 2004-02-05 2012-01-18 Probiodrug AG Novel inhibitors of glutaminyl cyclase
AU2005215775B2 (en) 2004-02-13 2011-02-03 Neuromolecular, Inc. Combination of a NMDA receptor antagonist and an anti-depressive drug MAO-inhibitor or a GADPH-inhibitor for the treatment of psychiatric conditions
US20050182044A1 (en) 2004-02-17 2005-08-18 Bruinsma Gosse B. Combinatorial therapy with an acetylcholinesterase inhibitor and (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3,-b]indol-5-yl phenylcarbamate
WO2005080435A1 (ja) 2004-02-20 2005-09-01 Immuno-Biological Laboratories Co., Ltd. モノクローナル抗体およびその利用
US20070213388A1 (en) 2004-03-19 2007-09-13 Bruinsma Gosse B Acetylcholinesterase Inhibitors and N-Methyl-D-Aspartate Antagonists Useful in the Treatment of of Cognitive Disorders
JP4211648B2 (ja) 2004-03-22 2009-01-21 日本電気株式会社 ソフトウェアインストール方法およびシステム
WO2005097103A2 (en) 2004-04-01 2005-10-20 Axys Pharmaceuticals, Inc. Diabetes and metabolic syndrome therapy utilizing cathepsin b inhibitors
AU2005230681B2 (en) 2004-04-05 2009-07-30 Schering Corporation Novel gamma secretase inhibitors
US7847100B2 (en) 2004-04-20 2010-12-07 Merck, Sharp & Dohme, Inc. 1,3,5-substituted phenyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease
EP1740581B1 (en) 2004-04-20 2012-08-22 Merck Sharp & Dohme Corp. 2, 4, 6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
WO2005102390A2 (en) 2004-04-22 2005-11-03 Pfizer Japan, Inc. Combinations comprising alpha-2-delta ligands and nmda receptor antagonists
US9549895B2 (en) 2004-04-23 2017-01-24 Massachusetts Eye And Ear Infirmary Methods and compositions for preserving the viability of photoreceptor cells
CA2564432A1 (en) 2004-04-27 2005-11-10 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Human anti-amyloid .beta. peptide antibody and fragment of said antibody
US7449599B2 (en) 2004-05-13 2008-11-11 Merck + Co Inc. Phenyl carboxamide compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
DE602005022871D1 (de) 2004-06-07 2010-09-23 Univ Ramot Verfahren zur passiven immunisierung gegen eine durch amyloidaggregation gekennzeichnete krankheit oder erkrankung mit vermindertem nervenentzündungsrisiko
EP1758854B1 (en) 2004-06-15 2014-07-16 Merck Sharp & Dohme Corp. Pyrrolidin-3-yl compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
SE0401601D0 (sv) 2004-06-21 2004-06-21 Bioarctic Neuroscience Ab Protofibril specific antibodies and uses thereof
CA2572289A1 (en) 2004-06-30 2006-08-17 Centocor, Inc. Anti-mcp-1 antibodies, compositions, methods and uses
CA2570183A1 (en) 2004-06-30 2006-01-12 Schering Corporation Substituted n-arylsulfonylheterocyclic amines as gamma-secretase inhibitors
WO2006014478A1 (en) 2004-07-02 2006-02-09 Northwestern University MONOLOCAL ANTIBODIES THAT TARGET PATHOLOGICAL ASSEMBLIES OF AMYLOID β (ABETA)
US20080038192A1 (en) 2004-07-19 2008-02-14 Neurochem Inc. Diagnostic Methods Of Multiple Organ Amyloidosis
WO2006014638A2 (en) 2004-07-19 2006-02-09 The General Hospital Corporation ANTIBODIES TO CROSS-LINKED AMYLOID β OLIGOMERS
AR049726A1 (es) 2004-07-22 2006-08-30 Schering Corp Amidas sustituidas inhibidoras de beta secretasa
ATE396990T1 (de) 2004-07-28 2008-06-15 Schering Corp Makrocyclische inhibitoren der beta-sekretase
HUP0401523A3 (en) 2004-07-29 2007-05-02 Richter Gedeon Vegyeszet Indole-2-carboxamide derivatives, pharmaceutical compositions containing them and process for producing them
MX2007000998A (es) 2004-07-30 2007-07-11 Rinat Neuroscience Corp Anticuerpos dirigidos peptido beta-amiloide y procedimientos que usan los mismos.
JP4820757B2 (ja) 2004-08-11 2011-11-24 国立大学法人京都大学 抗体及びその利用
US20070293486A1 (en) 2004-08-25 2007-12-20 Santhera Pharmaceuticals (Schweiz) Ag Alpha-Keto Carbonyl Calpain Inhibitors
CA2577987A1 (en) 2004-08-25 2006-03-02 Santhera Pharmaceuticals (Schweiz) Ag Alpha-keto carbonyl calpain inhibitors
US7388007B2 (en) 2004-08-26 2008-06-17 Bristol-Myers Squibb Company Gamma-lactams as beta-secretase inhibitors
US7335491B2 (en) 2004-08-27 2008-02-26 Wyeth Research Ireland Limited Production of anti-abeta
JP2008513364A (ja) 2004-09-14 2008-05-01 ザ ジェネティクス カンパニー，インコーポレイテッド ヒドラゾン誘導体およびβ−セクレターゼインヒビターとしてのその使用
EP1797052A1 (en) 2004-09-17 2007-06-20 Comentis, Inc. Bicyclic compounds which inhibit beta-secretase activity and methods of use thereof
CA2580265A1 (en) 2004-09-17 2006-03-30 Comentis, Inc. Amino-containing compounds which inhibit memapsin 2 beta-secretase activity and methods of use thereof
US20060246075A1 (en) 2004-09-29 2006-11-02 Marc Mercken Anti-amyloid antibodies, compositions, methods and uses
WO2006042103A2 (en) 2004-10-05 2006-04-20 Axys Pharmaceuticals, Inc. Reversible inhibitors of cathepsin b
EP2008660A1 (en) 2004-10-12 2008-12-31 Ernir Snorrason Inhibitors of acetylcholinesterase for treating skin diseases
JP2008515989A (ja) 2004-10-13 2008-05-15 メルク エンド カムパニー インコーポレーテッド アルツハイマー病を治療するためのβ−セクレターゼ阻害薬として有用なスピロピペリジン化合物
CA2626049A1 (en) 2004-10-15 2006-04-20 Biopharmacopae Design International Inc. Methods and therapeutic compositions comprising plant extracts for the treatment of cancer
NZ554725A (en) 2004-10-25 2009-10-30 Merck & Co Inc Anti-ADDL antibodies and uses thereof
RU2007119535A (ru) 2004-10-28 2008-12-10 ЭЙСАЙ Р энд Д МЕНЕДЖМЕНТ КО. Способ тестирования болезни альцгеймера и диагностический реагент
US7932275B2 (en) 2004-10-29 2011-04-26 Merck, Sharp & Dohme Corp. 2-aminopyridine compounds useful as β-secretase inhibitors for the treatment of alzheimer's disease
CA2587083A1 (en) 2004-11-17 2006-05-26 Merck & Co., Inc. Macrocyclic tertiary amine beta-secretase inhibitors for the treatment of alzheimer's disease
JP4235162B2 (ja) 2004-11-18 2009-03-11 日本電信電話株式会社 画像符号化装置，画像符号化方法，画像符号化プログラムおよびコンピュータ読み取り可能な記録媒体
US8394837B2 (en) 2004-11-23 2013-03-12 Merck, Sharp & Dohme, Corp. 2,3,4,6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
CN101061119A (zh) 2004-11-23 2007-10-24 默克公司 治疗阿尔茨海默氏病的大环氨基吡啶β－分泌酶抑制剂
AU2005309601A1 (en) 2004-11-23 2006-06-01 Neuromolecular Pharmaceuticals, Inc. Composition comprising a sustained release coating or matrix and an NMDA receptor antagonist, method for administration such NMDA antagonist to a subject
EP1845968A2 (en) 2004-11-24 2007-10-24 Neuromolecular Pharmaceuticals, Inc Composition comprising an nmda receptor antagonist and levodopa and use thereof for treating neurological disease
US20080139458A1 (en) 2004-12-03 2008-06-12 Jay Gregory D Methods of Treatment For Injured or Diseased Joints
WO2006066049A2 (en) 2004-12-15 2006-06-22 Neuralab Limited Humanized antibodies that recognize beta amyloid peptide
EP1838349A1 (en) 2004-12-15 2007-10-03 Neuralab, Ltd. Amyloid beta antibodies for use in improving cognition
TW200635607A (en) 2004-12-15 2006-10-16 Elan Pharm Inc Humanized Aβ antibodies for use in improving cognition
US20060240486A1 (en) 2004-12-15 2006-10-26 Johnson-Wood Kelly L Immunoprecipitation-based assay for predicting in vivo efficacy of beta-amyloid antibodies
EP2425846A1 (en) 2004-12-23 2012-03-07 Voyager Pharmaceutical Corporation Acetylcholinesterase Inhibitors and leuprolide acetate for the treatment of Alzheimer's disease
EP1831172B1 (en) 2004-12-28 2009-02-18 Council of Scientific and Industrial Research Substituted carbamic acid quinolin-6-yl esters useful as acetylcholinesterase inhibitors
JP2008526861A (ja) 2005-01-06 2008-07-24 メルク エンド カムパニー インコーポレーテッド 炎症性障害を治療するための薬剤併用療法および医薬組成物
WO2006078576A2 (en) 2005-01-19 2006-07-27 Merck & Co., Inc. Aminomethyl beta-secretase inhibitors for the treatment of alzheimer's disease
EP1841455A1 (en) 2005-01-24 2007-10-10 Amgen Inc. Humanized anti-amyloid antibody
TW200640529A (en) 2005-02-28 2006-12-01 Thomas Christian Lines Composition for treating mental health disorders
EP1858501A1 (en) 2005-03-07 2007-11-28 Michael Hermanussen Nmda receptor antagonists in the medical intervention of metabolic disorders
ES2259270B1 (es) 2005-03-09 2007-11-01 Consejo Superior De Investigaciones Cientificas Metodo de diagnostico in vitro de la enfermedad de alzheimer mediante un anticuerpo monoclonal.
US7745470B2 (en) 2005-03-10 2010-06-29 Bristol-Myers Squibb Company Isophthalates as beta-secretase inhibitors
FR2883285B1 (fr) 2005-03-17 2007-05-18 Sanofi Aventis Sa Sel besylate de la 7-(2-(4-(3-trifluoromethyl-phenyl) -1,2,3,6-tetrahudro-pyrid-1-yl)ethyl) isoquinoleine, sa preparation et son utilisation en therapeutique
ES2318918B1 (es) 2005-04-01 2010-02-16 Biotherapix Molecular Medicines, S.L.U. Anticuerpos humanos con capacidad de union al peptido beta-amiloide y sus aplicaciones.
JP2008535892A (ja) 2005-04-11 2008-09-04 プロビオドルグ エージー プロリルエンドペプチダーゼの阻害剤
AU2006241219A1 (en) 2005-04-27 2006-11-02 Novartis Ag Methods of treating atherosclerosis
MY148086A (en) 2005-04-29 2013-02-28 Rinat Neuroscience Corp Antibodies directed against amyloid-beta peptide and methods using same
TW200716174A (en) 2005-05-19 2007-05-01 Centocor Inc Anti-MCP-1 antibodies, compositions, methods and uses
EP1921137A4 (en) 2005-06-21 2011-01-26 Med & Biological Lab Co Ltd ANTIBODIES WITH INHIBITOR EFFECT ON THE FORMATION OF AMYLOID FIBRILLES
MY181173A (en) 2005-12-12 2020-12-21 Ac Immune Sa Therapeutic vaccine
ES2454253T3 (es) 2005-12-12 2014-04-10 Ac Immune S.A. Anticuerpos monoclonales específicos de beta A 1-42 con propiedades terapéuticas
GB0704100D0 (en) 2006-03-17 2007-04-11 Vodafone Plc Improvements in an ehspa architecture
KR101605207B1 (ko) 2006-07-14 2016-03-22 에이씨 이뮨 에스.에이. 아밀로이드 베타에 대해 인간화된 항체

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5100909A (en) * 1988-07-25 1992-03-31 The Upjohn Company Acetylenic imidazoles having central nervous system activity
WO1997043278A1 (en) * 1996-05-14 1997-11-20 Novo Nordisk A/S Somatostatin agonists and antagonists
WO2002096869A2 (en) * 2001-05-29 2002-12-05 Peking University School Of Pharmaceutical Sciences Piperazine mono(dithio)carbamate ester compounds and analogs thereof
WO2003022273A1 (en) * 2001-09-13 2003-03-20 Boehringer Ingelheim Pharmaceuticals, Inc. Methods of treating cytokine mediated diseases
US20030166644A1 (en) * 2001-12-14 2003-09-04 Soren Ebdrup Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
US20070191366A1 (en) * 2003-05-05 2007-08-16 Torsten Hoffmann Use of effectors of glutaminyl and glutamate cyclases

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BHATIA MADHAV ET AL: "Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis", AMERICAN JOURNAL OF PHYSIOLOGY - GASTROINTESTINAL AND LIVER PHYSIOLOGY, vol. 288, no. 6, June 2005 (2005-06-01), pages G1259 - G1265, XP008120185, ISSN: 0193-1857, DOI: doi:10.1152/ajpgi.00435.2004 *
GALIMBERTI D ET AL: "Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease", NEUROBIOLOGY OF AGING, TARRYTOWN, NY, US, vol. 27, no. 12, 1 December 2006 (2006-12-01), pages 1763 - 1768, XP024993074, ISSN: 0197-4580, [retrieved on 20061201], DOI: DOI:10.1016/J.NEUROBIOLAGING.2005.10.007 *
MARRA F: "Renaming cytokines: MCP-1, major chemokine in pancreatitis", GUT, vol. 54, no. 12, December 2005 (2005-12-01), pages 1679 - 1681, ISSN: 0017-5749 *
MORI EMIKO ET AL: "Essential role of monocyte chemoattractant protein-1 in development of restenotic changes (Neointimal hyperplasia and constrictive remodeling) after balloon angioplasty in hypercholesterolemic rabbits", CIRCULATION, vol. 105, no. 24, 18 June 2002 (2002-06-18), pages 2905 - 2910, ISSN: 0009-7322 *
SCHILLING S ET AL: "Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions", FEBS LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 563, no. 1-3, 9 April 2004 (2004-04-09), pages 191 - 196, XP004501117, ISSN: 0014-5793, DOI: DOI:10.1016/S0014-5793(04)00300-X *
See also references of WO2008104580A1 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives

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