Imidamide sphingosine kinase inhibitors
Imidamide (amidine) analogs that can inhibit the activity of sphingosine kinase 1 and sphingosine kinase 2 (SphK1 & SphK2) are provided. The compounds can prevent angiogenesis in tumors.
1. A compound of formula IA:
wherein
R 1 is hydrogen or OH;
Y is C═O (carbonyl);
Z is
A. (C 12 -C 20 )alkylaryl, wherein Z is optionally substituted with a (C 6 -C 10 )alkoxycycloalkyl, (C 6 -C 10 )alkoxyphenyl, phenyl, or a (C 3 -C 7 )cycloalkyl;
B. (C 5 -C 12 )alkyl-4-phenyl substituted with (C 5 -C 10 )cycloalkyl—O; or
C. a substituent selected from the group consisting of
or a pharmaceutically acceptable salt or ester thereof.
2. The compound of claim 1 , wherein R 1 is hydrogen.
3. The compound of claim 1 , wherein R 1 is —OH.
4. The compound of claim 1 , wherein Z is
5. A compound having the formula:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , having the formula:
7. A compound of claim 1 , which inhibits the activity of SphK1 and SphK2.
8. A compound of claim 1 , which selectively inhibits SphK1.
9. A compound of claim 1 , which selectively inhibits SphK2.
10. A pharmaceutical composition comprising a compound having the formula of claim 1 or 5 , and a pharmaceutically acceptable carrier.
11. The composition of claim 10 , wherein the composition is in the form of a kit.