Inhibitors of Rho associated protein kinases (ROCK) and methods of use
Compounds and compositions having activity as inhibitors of Rho-associated proteinkinases (ROCKs), and methods of making and using the subject compounds are disclosed.
1. A method of reducing or inhibiting tumor growth in a subject with breast cancer, comprising: administering to the subject an effective amount of a composition comprising a compound having the chemical structure shown in Formula IV
wherein
R is H, alkyl, acetyl, or heteroalkyl;
R 1 is H, alkyl, acetyl, or heteroalkyl;
R 8 and R 9 are, independently of one another, H, —OH, acetyl, —C(O)NH 2 , alkyl, cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl, wherein any one of the alkyl, cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more of —OH, —NO 2 , —NH 2 , —NR 6 R 7 , carbonyl, alkoxy, alkyl, —OCX 3 , —OCHX 2 , —OCH 2 X, or halogen, or both R 8 together form a carbonyl; and
R 10 is cycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more of —OH, —C(O)NH 2 , —C(O)CH 3 , —NO 2 , —NH 2 , —NR 6 R 7 , carbonyl, alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, halogenated alkoxyl, cycloalkyl, heterocycloalkyl, heteroarylcarbonyl, aryl, heteroaryl, —OCX 3 , —OCHX 2 , —OCH 2 X, —OSO 2 CH 3 , or -tosyl;
R 6 and R 7 are, independently, H, alkyl, —SO 2 CH 3 , —C(O)CH 3 , or —C(O)NH 2 ;
X is independently H or halogen; and
n is 2 or 3,
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein n is 2.
3. The method of claim 1 , wherein R 8 and R 9 are, independently, H, alkyl, or alkyl substituted with —OH, —NH 2 , alkoxy, or halogen.
4. The method of claim 1 , wherein R 10 is an aryl or heteroaryl, any of which is optionally substituted in the ortho-, meta-, or para-position with —OH, —CO 2 CH 3 , —C(O)NH 2 , —NO 2 , —NH 2 , —NR 6 R 7 , alkoxy, alkylalkoxy, alkyl, —OSO 2 CH 3 , or tosyl.
5. The method of claim 1 , wherein the compound has the formula
6. The method of claim 1 , wherein the cancer is breast cancer.
7. The method of claim 1 , further comprising administering a second anticancer agent or an anti-inflammatory agent to the subject.
8. The method of claim 1 , further comprising administering Y27632, Wf536, Fasudil, H-1152P, and/or CID5056270 to the subject.
9. The method of claim 1 , further comprising administering an effective amount of ionizing radiation to the subject.
10. A method of reducing or inhibiting tumor growth in a subject with breast cancer, comprising: administering to the subject an effective amount of a composition comprising a compound having the chemical structure shown in Formula I
wherein
Z is CR or N;
R is H, alkyl, acetyl, or heteroalkyl;
R 1 is H, alkyl, acetyl, or heteroalkyl;
R 2 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkylaryl, any of which can be optionally substituted with one or more of —OH, —CH 2 OH, —C(O)NH 2 , acetyl, carbonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of —OH, —NO 2 , —NH 2 , —NR 6 R 7 , alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, halogenated alkoxy, heteroarylcarbonyl, heteroaryl, —OCX 3 , —OCHX 2 , —OCH 2 X, —OSO 2 CH 3 , tosyl, or halogen; or
R 1 and R 2 can together form a cycloalkyl or heterocycloalkyl
R 6 and R 7 are, independently, H, alkyl, —SO 2 CH 3 , —C(O)CH 3 , or —C(O)NH 2 ;
X is independently H or halogen;
with the proviso that R and R 1 are not both H when R 2 is CH(CH 2 OH)Ph;
or a pharmaceutically acceptable salt or hydrate thereof.
11. The method of claim 10 , wherein the compound has the chemical structure shown in Formula III
wherein
R 8 and R 9 are, independently of one another, H, —OH, acetyl, —C(O)NH 2 , alkyl, cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl, wherein any one of the alkyl, cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more of —OH, —NO 2 , —NH 2 , —NR 6 R 7 , carbonyl, alkoxy, alkyl, —OCX 3 , —OCHX 2 , —OCH 2 X, or halogen, or both R 8 together form a carbonyl; and
R 10 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more of —OH, —C(O)NH 2 , —C(O)CH 3 , —NO 2 , —NH 2 , —NR 6 R 7 , carbonyl, alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, halogenated alkoxyl, cycloalkyl, heterocycloalkyl, heteroarylcarbonyl, aryl, heteroaryl, —OCX 3 , —OCHX 2 , —OCH 2 X, —OSO 2 CH 3 , -tosyl, or halogen; and
n is 1, 2, or 3.
12. The method of claim 10 , wherein n is 1 or 2.
13. The method of claim 10 , wherein R 8 and R 9 are, independently, H, alkyl, or alkyl substituted with —OH, —NH 2 , alkoxy, or halogen.
14. The method of claim 10 , wherein n is 1, and CR 8 R 9 is the R isomer of CHalkyl, wherein the alkyl group is substituted with —OH, NH 2 , alkoxy, or halogen.
15. The method of claim 10 , wherein n is 1, and CR 8 R 9 is the S isomer of CHalkyl, wherein the alkyl group is substituted with —OH, NH 2 , alkoxy, or halogen.
16. The method of claim 10 , wherein R 10 is an aryl or heteroaryl, any of which is optionally substituted in the ortho-, meta-, or para-position with —OH, —CO 2 CH 3 , —C(O)NH 2 , —NO 2 , —NH 2 , —NR 6 R 7 , alkoxy, alkylalkoxy, alkyl, —OSO 2 CH 3 , tosyl, or halogen.
17. The method of claim 10 , wherein (CR 8 R 9 ) n R 10 have the combined structure:
18. The method of claim 10 , where the compound is
19. The method of claim 10 , further comprising administering a second anticancer agent or an anti-inflammatory agent to the subject.
20. The method of claim 10 , further comprising administering Y27632, Wf536, Fasudil, H-1152P, and/or CID5056270 to the subject.
21. The method of claim 10 , further comprising administering an effective amount of ionizing radiation to the subject.