Use of effectors of glutaminyl and glutamate cyclases
AssigneeProbiodrug AG
InventorsTorsten Hoffmann, Stephan Schilling, Andre Niestroj, Hans-Ulrich Demuth, Ulrich Heiser, Mirko Buchholz
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Abstract
The present invention provides novel physiological substrates of mammalian glutaminyl cyclase (QC, EC 2.3.2.5), new effectors of QC, methods for screening for such effectors, and the use of such effectors and pharmaceutical compositions comprising such effectors for the treatment of conditions that can be treated by modulation of QC-activity. Preferred compositions additionally comprise inhibitors of DP IV or DP IV-like enzymes for the treatment or alleviation of conditions that can be treated by modulation of QC- and DP IV-activity.
Claims26
A method of treating diseases in mammals, comprising administering to said mammals a therapeutically effective amount of at least one effector of glutaminyl cyclase (QC) for modulating the conversion of N-terminal glutamic acid or glutamine residues to pyroglutamyl residues in at least one QC-substrate, wherein said disease is selected from the group consisting of
- 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, and
- f) other inflammatory diseases, e.g. neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis.
A pharmaceutical composition for parenteral, enteral or oral administration, comprising at least one inhibitor of QC optionally in combination another agent.
A screening method for the identification and selection of effectors of QC comprising the following steps:
- a) Contacting said compounds with QC under conditions, which would permit binding there between;
- b) Adding a substrate of QC;
- c) Monitoring the conversion of the substrate or optionally measuring the residual QC activity;
- and
- d) Calculating changes in the substrate conversion and/or enzyme activity of QC to identify an activity modifying effector of QC.
A screening method for the identification and selection of effectors which interact directly or indirectly with the active-site bound metal ion of QC comprising the following steps:
- a) Contacting said compounds with QC under conditions which would permit binding therebetween;
- b) Adding a substrate of QC which is subject to conversion by QC;
- c) Monitoring the conversion of the substrate or optionally measuring the residual QC activity;
- and
- d) Calculating changes in the substrate conversion and/or enzyme activity of QC wherein changes may be used to identify an activity modifying effector of QC.
Dependencies are inferred from the claim text.