Class of HDAC inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury
Compounds and compositions are provided that inhibit histone deacylase activity and which expand renal progenitor cell populations and improve kidney function in a damaged kidney. Methods of use of the compounds and compositions are provided.
1. A compound having the formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , selected from the group consisting of,
or a pharmaceutically acceptable salt thereof.
5. A compound having the formula:
in which
R is O,
R1 is methoxy or —NHR4 where R4 is OH, aminophenyl, hydroxyphenyl, hydroxypyridinyl, aminopyridinyl, alkyl hydroxypyridinyl, or haloalkyl hydroxyphenyl,
R2 is phenyl, benzyl, 4-methoxybenzyl, phenylethyl, substituted phenyl having the structure
where R5 is methylthio, methylsulfonyl, methylsulfinyl, acetyl, 2-acetato, 3-acetato, methyl carbamoyl, or methoxycarbonyl and
R3 is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —,
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , in which R3 is —CH 2 —CH 2 —CH 2 —or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —.
7. The compound of claim 5 , in which R3 is —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —.
8. The compound of claim 5 , in which R1 is methoxy.
9. The compound of claim 5 , in which R2 is benzyl, 4-methoxybenzyl, or phenylethyl.
10. The compound of claim 5 , in which R2 is
where R5 is methylthio, methylsulfonyl, methylsulfinyl, acetyl, 2-acetato, 3-acetato, methyl carbamoyl, or methoxycarbonyl.
11. The compound of claim 5 , selected from the group consisting of,
or a pharmaceutically acceptable salt thereof.
12. A compound having the formula:
in which
R is S,
R1 is NHR4 where R4 is hydroxypyridinyl, aminopyridinyl, alkyl hydroxypyridinyl, or haloalkyl hydroxyphenyl, and
R2 is phenyl, benzyl, 4-methoxybenzyl, phenylethyl, or substituted phenyl having the structure
where R5 is 3-hydroxyl, methylthio, methylsulfonyl, methylsulfinyl, acetyl, 2-acetato, 3-acetato, carbamoyl, methyl carbamoyl, or methoxycarbonyl, and
R3 is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —,
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , in which R3 is —CH 2 —CH 2 —CH 2 —or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —.
14. The compound of claim 12 , in which R2 is benzyl, phenylethyl, 4-methoxybenzyl, or
where R5 is 3-hydroxyl, acetyl, 2-acetato, 3-acetato, carbamoyl, methyl carbamoyl, or methoxycarbonyl.
15. The compound of claim 12 , selected from the group consisting of,
or a pharmaceutically acceptable salt thereof.
16. A compound having the formula:
in which
R is S,
R1 is NHR4 where R4 is hydroxyphenyl or aminophenyl, and
R2 is substituted phenyl having the structure
where R5 4-acetato,
R3 is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —,
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 16 , in which R3 is —CH 2 —CH 2 —CH 2 —or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —.
18. A compound having the formula:
in which
R is S,
R1 is methoxy or —NHR4 where R4 is OH, aminophenyl, hydroxyphenyl, hydroxypyridinyl, aminopyridinyl, alkyl hydroxypyridinyl, or haloalkyl hydroxyphenyl,
R2 is benzyl, phenylethyl, 4-methoxybenzyl, or
where R5 is 3-hydroxyl, acetyl; 2-acetato, 3-acetato, carbamoyl, methyl carbamoyl, or methoxycarbonyl, and
R3 is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —,
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 18 , in which R3 is —CH 2 —CH 2 —CH 2 —or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —.
20. The compound of claim 18 , in which R1 is methoxy.
21. The compound of claim 18 , selected from the group consisting of,
or a pharmaceutically acceptable salt thereof.
22. A compound having the formula:
in which
R is S(O) or S(O) 2
R1 is methoxy or —NHR4 where R4 is OH, aminophenyl, hydroxyphenyl, hydroxypyridinyl, aminopyridinyl, alkyl hydroxypyridinyl, or haloalkyl hydroxyphenyl,
R2 is benzyl, phenylethyl, or methylsulfonylphenyl and
R3 is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —,
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 22 , in which R3 is —CH 2 —CH 2 —CH 2 —or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —.
24. The compound of claim 22 , in which R1 is methoxy.
25. The compound of claim 22 , selected from the group consisting of,
or a pharmaceutically acceptable salt thereof.
26. A compound having the formula:
in which
R is P(O)(CH 3 ) or P(O)(OCH 3 ),
R1 is methoxy or —NHR4 where R4 is OH, aminophenyl, hydroxyphenyl, hydroxypyridinyl, aminopyridinyl, alkyl hydroxypyridinyl, or haloalkyl hydroxyphenyl,
R2 is phenyl, benzyl, 4-methoxybenzyl, phenylethyl, substituted phenyl having the structure
where R5 is 3-hydroxyl, methylthio, methylsulfonyl, methylsulfinyl, acetyl, 2-acetato, 3-acetato, carbamoyl, methyl carbamoyl, or methoxycarbonyl and
R3 is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —,
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 26 , in which R3 is —CH 2 —CH 2 —CH 2 —or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —.
28. The compound of claim 26 , in which R1 is methoxy.
29. The compound of claim 26 , in which R2 is benzyl, 4-methoxybenzyl, or phenylethyl.
30. The compound of claim 26 , in which R2 is
where R5 is 3-hydroxyl, methylthio, methylsulfonyl, methylsulfinyl, acetyl, 2-acetato, 3-acetato, carbamoyl, methyl carbamoyl, or methoxycarbonyl.
31. The compound of claim 26 , selected from the group consisting of,
or a pharmaceutically acceptable salt thereof.