Vitamin receptor drug delivery conjugates for treating inflammation
Described herein are compositions, methods, compounds, conjugates, and kits for use in targeted drug delivery using drug delivery conjugates containing hydrophilic spacer linkers for use in treating disease states caused by pathogenic cell populations, such as inflammatory cells.
1. A compound of the formula
BLA
or a pharmaceutically acceptable salt thereof; wherein
B is a vitamin receptor binding ligand;
L is a linker that comprises one or more hydrophilic spacer linkers selected from the group consisting of
wherein
R is selected from the group consisting of H, alkyl, cycloalkyl, and arylalkyl; m is an integer from 1 to about 3; n is an integer from 1 to about 6; p is an integer from 1 to about 5; and (*) indicates the point of attachment to the rest of the compound and
a fragment of the formula
wherein
each R a and R b is independently hydrogen or alkyl; or R a and R b are taken together with the attached carbon atom to form a carbocyclic ring;
n 1 is an integer selected from 1 to 4; and
(**) indicates points of attachment for other parts of the conjugate; and
A is an anti-inflammatory agent.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the anti-inflammatory agent is an antifolate.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the linker comprises three hydrophilic spacer linkers.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the one or more hydrophilic spacer linkers each comprise five hydroxyl groups.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the linker further comprises one or more amino acids selected from the group consisting of the naturally occurring amino acids and stereoisomers thereof.
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein the linker further comprises one or more amino acids selected from the group consisting of asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, and stereoisomers thereof.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the linker further comprises a releasable linker.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the linker further comprises a disulfide group.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the purity of the compound is at least 98%.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding ligand is a folate.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding ligand is of the formula
wherein * indicates the point of attachment to the linker.
12. A pharmaceutical composition comprising a compound of the formula
BLA
or a pharmaceutically acceptable salt thereof; wherein
B is a vitamin receptor binding ligand;
L is a linker that comprises one or more hydrophilic spacer linkers selected from the group consisting of
wherein
R is selected from the group consisting of H, alkyl, cycloalkyl, and arylalkyl; m is an integer from 1 to about 3; n is an integer from 1 to about 6; p is an integer from 1 to about 5; and (*) indicates the point of attachment to the rest of the compound and
a fragment of the formula
wherein
each R a and R b is independently hydrogen or alkyl; or R a and R b are taken together with the attached carbon atom to form a carbocyclic ring;
n 1 is an integer selected from 1 to 4; and
(**) indicates points of attachment for other parts of the conjugate; and
A is an anti-inflammatory agent.
13. The pharmaceutical composition of claim 12 , wherein, in the compound, or the pharmaceutically acceptable salt thereof, the vitamin receptor binding ligand is a folate and the anti-inflammatory agent is an antifolate.
14. The pharmaceutical composition of claim 12 , further comprising one or more carriers, diluents, or excipients, or a combination thereof.
15. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the antifolate is aminopterin, or an analogue or derivative thereof.
16. The compound of claim 1 , wherein the compound is