Molecules inhibiting a metabolic pathway involving the syk protein tyrosine kinase and method for identifying said molecules
AssigneeCentre National De La Recherche Scientifique
InventorsPiona Dariavach, Pierre Emile Ulysse Martineau, Bruno Villoutreix
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Abstract
The present invention relates to the C-13 molecule (methyl 2-{5-[(3-benzyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]-2-furyl}-benzoate) and to organic molecules functionally equivalent to the C-13 molecule, capable of inhibiting the binding of an antibody or antibody fragment with the human Syk protein tyrosine kinase, to the use of these molecules for the production of medicaments for the prevention or treatment of diseases dependent on metabolic pathways involving Syk, and also to a method for identifying such molecules.
Claims22
1-30. (canceled)
A method for preventing or treating a condition dependent on a metabolic pathway involving Syk in a human or an animal, which comprises administering to the human or animal a compound which (a) binds with Syk tyrosine kinase protein of a three-dimensional cavity comprising the arginine residue situated in position 68 and the two glutamic acid residues situated in positions 121 and 155 of human Syk tyrosine kinase protein, the sequence of which is set forth in SEQ ID No:
- 1, and (b) is capable of inhibiting by at least 10% in vitro binding of
- (i) antibody fragment G4G11 (SEQ ID No:
- 2), or
- (ii) an antibody or antibody fragment which bind with human Syk tyrosine kinase protein at an epitope comprising at least one of residues 65 to 74 of the amino acid sequence of human Syk tyrosine kinase protein (SEQ ID No:
- 1), or
- (iii) an antibody or antibody fragment which binds with human Syk tyrosine kinase protein and inhibits by at least 10% the binding of antibody fragment G4G11 with human Syk tyrosine kinase protein (SEQ ID No;
- 1),
- with human Syk tyrosine kinase protein or with a variant thereof in animals, wherein said compound has the formula
- or is an organic compound functionally equivalent to compound C-13 having a molecular weight between 50 and 2500 Dalton, selected from (a) derivatives of C13, wherein one or more atoms belonging to a carbon chain, an aromatic group, a cycle or a heterocycle of C13 is or are substituted via a covalent bond by one or a plurality of halogens, and/or by one or a plurality of aromatic, cyclic, heterocyclic, alkyl, alkoxy, carboxyl, carbonyl, primary, secondary or tertiary amine, amide or sulphonamide groups;
- or (b) compounds having any of the following formulae:
- where
- R1 is an unsubstituted or substituted aromatic group, or an unsubstituted or substituted heterocycle comprising at least one S, O or N atom;
- R2 is an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocycle, an unsaturated or saturated carbon chain comprising an amine group, an unsaturated or saturated carbon chain comprising an unsubstituted or substituted aromatic group or an unsaturated or saturated carbon chain comprising an unsubstituted or substituted heterocycle comprising at least one S, O or N atom;
- R3 is an unsubstituted or substituted phenyl, 2-pyridinyl, 3 pyridinyl or 4-pyridinyl group,
- or
- where
- n=0 or 1;
- n′=0 or 1;
- R4 is an unsaturated or saturated carbon chain comprising 1 to 5 carbon atoms, unsubstituted or substituted with an aromatic group;
- R5 is an unsubstituted or substituted aromatic group or an unsubstituted or substituted amine group;
- R6 is a hydrogen atom, an alkoxy group, an alkyl group or a halogen;
- R7 is a hydrogen atom, an alkoxy group, an alkyl group or a halogen;
- R8 is a hydrogen atom, an alkoxy group, an alkyl group or a halogen;
- or
- where
- m 0, 1 or 2;
- R9 is a hydrogen atom and R10 is an unsubstituted or substituted phenyl group, or R9 and R10 are part of the same unsubstituted or substituted heterocycle, or R9 and R10 are part of the same unsubstituted or substituted aromatic group;
- R11 is a hydrogen atom, an alkoxy group or an alkyl group;
- R12 is a hydrogen atom, an alkoxy group or an alkyl group;
- R13 is a hydrogen atom or an alkyl or alkoxy group;
- R14 is a hydrogen atom or an alkyl or alkoxy group;
- or
- where
- A is an oxygen or sulphur atom;
- R15 is an unsaturated or saturated carbon chain comprising 1, 2 or 3 carbon atoms, unsubstituted or substituted by an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocycle or an amine group belonging to unsubstituted or substituted heterocycle;
- R16 is a hydrogen atom, a halogen or an alkoxy group;
- R17 is a hydrogen atom, an alkoxy group or an acetoxy group;
- or
- or a stereo-isomer, racemate or pharmacologically acceptable salt of C-13 or of said functionally equivalent compound and a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.