Small molecules that covalently modify transthyretin
AssigneeThe Scripps Research Institute
InventorsJeffery W Kelly, Sungwook Choi
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Abstract
A family of covalent kinetic stabilizer compounds that selectively and covalently react with the prominent plasma protein transthyretin in preference to more than 4000 other human plasma proteins is disclosed. A contemplated compound corresponds in structure to Formula I, below, where the various substituents are defined within, and reacts chemoselectively with one or two of four Lys-15 ε-amino groups within the transthyretin tetramer. The crystal structure confirms the binding orientation of the compound substructure and the conjugating amide bond. A covalent transthyretin kinetic stabilizer exhibits superior amyloid inhibition potency, compared to a non-covalent counterpart, and inhibits cytotoxicity associated with amyloidogenesis.
Claims10
A compound corresponding in structure to Formula I
- wherein
- R1 is a halide, a methyl, monofluoro-, difluoro- or trifluoromethyl group;
- R2 is H, OH or NH2;
- n is one;
- L is CH2—CH2 or HC═CH;
- Z is H;
- C(O)—R is a carboxylic acid ester or thioester whose R group is prepared using a phenyl, pyridinyl or pyrimidinyl alcohol or thiol,
- the circle A is an aromatic or heteroaromatic ring structure containing one 5- or 6-membered ring or a fused ring system containing one 5- and one 6-membered ring or two 6-membered rings, wherein the bonds to L and C(O)—R are in a 1,3-substitution relationship on the ring to which they are bonded such that circle A linked to C(O)—R forms a ring structure selected from the group consisting of
A compound that corresponds in structure to one or more of the structural formulas shown below
Dependencies are inferred from the claim text.