Methods and compositions for treating diseases and disorders associated with Siglec-8 expressing cells
The invention provides therapeutic methods and compositions for the prevention and treatment of Siglec-8 associated diseases and disorders such as asthma and allergic reactions. In particular, the invention provides methods and compositions for the prevention and treatment of diseases and disorders associated with Siglec-8 expressing cells in humans, as well as other animals, through the administration of one or more novel, carbohydrate-based compounds.
1. The compound NeuAcα2-3(6-O-sulfo)Galβ1-4(Fucα1-3)GlcNAcβ-O—(CH 2 ) 3 —NH—CO(CH 2 ) 5 NH-M, where M is a hydrogen or amide linkage; or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising any of the compounds of claim 1 and a pharmaceutically acceptable solvent.
3. A method for treating a subject suffering from or susceptible to a disease or disorder involving activation of Siglec-8 on Siglec-8 expressing cells comprising administering to the subject an effective amount of one or more compounds represented by the formula:
in which
A is a sialic acid residue or an analog thereof;
B is a galactose residue or an analog thereof, and is substituted with an anionic moiety at the 6-position;
C is an N-acetylglucosamine residue or an analog thereof;
D is a fucose residue or an analog thereof; and
R together with the O atom to which it is attached, is an aglycone;
or a pharmaceutically acceptable salt thereof.
4. The method of claim 3 wherein the subject is suffering from or susceptible to asthma, allergic diseases, atopic dermatitis, hypereosinophilic syndromes, mastocytosis, leukemias, lymphomas, urticaria, Churg-Strauss syndrome, eosinophilic esophagitis, eosinophilic gastroenteritis, anaphylaxis, and nasal polyposis.
5. The method of claim 3 wherein the subject is a human.
6. A pharmaceutical composition kit comprising i) one or more compounds of claim 1 ; and ii) directions for use of the one or more compounds of claim 1 to treat a disease or disorder involving activation of Siglec-8 on Siglec-8 expressing cells.
7. A compound represented by the formula:
in which
A is a sialic acid residue or an analog thereof;
B is a galactose residue or an analog thereof, and is substituted with an anionic moiety at the 6-position;
C is an N-acetylglucosamine residue or an analog thereof;
D is a fucose residue or an analog thereof; and
wherein R, together with the O atom to which it is attached is an aglycone represented by the structure —O—(CH 2 ) 3 —NH—CO(CH 2 ) 5 NH-M, where M is a hydrogen or an amide linkage;
or a pharmaceutically acceptable salt thereof.
8. A compound represented by the formula:
wherein R together with the O atom to which it is attached is an aglycone represented by the structure —O—(CH 2 ) 3 —NH—CO(CH 2 ) 5 NH-M, where M is a hydrogen or an amide linkage; and
Y is independently for each occurrence an anionic group selected from the group consisting of carboxylate, sulfate, sulfonate, phosphate, phosphonate and hydroxamate;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound binds to Siglec-8 protein with an affinity of less than 10 μM.
10. The compound of claim 7 , wherein the compound binds to Siglec-8 protein with an affinity of less than 10 μM.
11. The compound of claim 8 , wherein the compound binds to Siglec-8 protein with an affinity of less than 10 μM.
12. A pharmaceutical composition comprising any of the compounds of claim 1 , 7 , or 8 ; and a pharmaceutically acceptable solvent.
13. A method for treating a subject suffering from or susceptible to a disease or disorder involving activation of Siglec-8 on Siglec-8 expressing cells comprising administering to the subject an effective amount of one or more compounds of claim 1 , 7 , or 8 .
14. The method of claim 13 wherein the subject is suffering from or susceptible to asthma, allergic diseases, atopic dermatitis, hypereosinophilic syndromes, mastocytosis, leukemias, lymphomas, urticaria, Churg-Strauss syndrome, eosinophilic esophagitis, eosinophilic gastroenteritis, anaphylaxis, and nasal polyposis.
15. The method of claim 13 wherein the subject is a human.
16. A pharmaceutical composition kit comprising
i) one or more compounds of claim 1 , 7 , or 8 ; and
ii) directions for use of the one or more compounds of claim 1 , 7 , or 8 to treat a disease or disorder involving activation of Siglec-8 on Siglec-8 expressing cells.