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Withdrawn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Withdrawn legal-status Critical Current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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KR20090115951A (ko) 2009-11-10
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AU2008220785A1 (en) 2008-09-04
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