Ziel
Inflammatory bowel diseases such as Crohn's disease still lack efficient, cost effective treatments. Using recent advances in drug design, the partners have identified a new therapeutic drug class that has the potential to cut annual treatment costs while offering a better level of treatment than is currently available. The goals of this proposal are, therefore to: Select and improve the new anti-inflammatory compounds using partner technologies Formulate them for use in the context of bowel disease Test them in advanced disease models Select a clinical candidate and demonstrate safety in standard toxicological models It is now clear that tumour necrosis factor (TNF) plays an important role in Crohn's disease pathology and reductions in the production of this cytokine result in disease remission.
TNF is produced in response to stimulation amplified via key signalling proteins including kinase enzymes and blockade of this enzyme is effective in preventing TNF production. The most abundant source of TNF is the activated macrophage, an immune cell that is accumulated in sites of chronic disease where a drug must act in order to reverse progress of disease. Optimal drug safety and efficacy will depend on maximising the amount of drug available to macrophage while limiting the overall dose and exposure to the rest of the body. The project, therefore, sets out to improve p38 kinase inhibitors using a combination of computer aided drug design, and a novel technology for assisting drug partition to macrophage. The partners will use high-resolution models of p38 kinase and selectively designed drug conjugates to identify potent new inhibitors of macrophage TNF production. These will be tested for activity in models of inflammatory bowel disease and progressed into pre-clinical development for eventual patient trials.
Wissenschaftliches Gebiet
- medical and health sciencesbasic medicinepharmacology and pharmacydrug safety
- medical and health sciencesbasic medicinemedicinal chemistry
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Aufforderung zur Vorschlagseinreichung
FP6-2003-SME-1
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