COMPOSITIONS AND TREATMENTS FOR INHIBITING KINASE AND/OR HMG-COA REDUCTASE
The present invention provides compositions of matter, kits and methods for their use in the treatment of MAP kinase-related conditions and/or HMG-CoA reductase-related conditions. In particular, the invention provides compositions for treating inflammatory and/or cardiovascular conditions in an animal subject by inhibiting p38α MAP kinase and/or HMG-CoA reductase, as well as providing formulations and modes of administering such compositions. The invention further provides methods for the rational design of inhibitors of MAP kinase, HMG-COA reductase, or both for use in the practice of the present invention.
1 . A method of inhibiting a MAP kinase comprising administering an effective amount of at least one compound comprising formula VII
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
R 3 is any substituent;
R 4 is optionally substituted
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof.
2 . The method as recited in claim 1 wherein said R 1 has the following stereochemistry:
3 . The method as recited in claim 1 wherein said inhibited MAP kinase is p38 MAP kinase.
4 . The method as recited in claim 1 , further comprising inhibiting an HMG CoA reductase.
5 . The method as recited in claim 1 wherein said administering treats a MAP kinase-related condition.
6 . The method as recited in claim 1 wherein said administering treats a MAP kinase-related condition and an HMG CoA reductase-related condition.
7 . The method as recited in claim 1 wherein said administering treats an inflammatory condition.
8 . A compound comprising formula VII:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
R 3 is any substituent;
R 4 is optionally substituted
optionally substituted
or substituted
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof.
9 . The compound as recited in claim 8 wherein R 2 is a C 3-4 branched alkyl group.
10 . The compound as recited in claim 8 wherein R 2 is isopropyl.
11 . The compound as recited in claim 8 wherein R 4 is
12 . The compound as recited in claim 8 wherein R 4 is
13 . The compound as recited in claim 8 wherein R 4 is
14 . The compound as recited in claim 8 wherein R 4 is
15 . The compound as recited in claim 8 wherein R 4 is
16 . The compound as recited in claim 8 wherein R 4 is
17 . The compound as recited in claim 8 wherein R 4 is
18 . The compound as recited in claim 8 wherein R 5 is an optionally substituted phenyl group.
19 . The compound as recited in claim 8 wherein R 5 is 4-fluorophenyl.
20 . The compound as recited in claim 8 wherein R5 is 3-trifluoromethylphenyl.
21 . The compound as recited in claim 8 wherein R 3 is —CONH— aryl.
22 . The compound as recited in claim 8 wherein R 3 is —CONH-phenyl.
23 - 26 . (canceled)
27 . A compound comprising formula VII:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
R 3 is any substituent;
R 4 is substituted
wherein said R 4 is substituted with one or more optionally substituted amino groups or optionally substituted alkoxy groups;
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof.
28 . A compound comprising formula VIIa:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
the pyridinyl ring is substituted;
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof.
29 . A compound comprising formula VIb:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
the pyrimidinyl ring is optionally substituted;
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof.
30 . A pharmaceutical composition comprising an effective amount of at least one compound as recited in claim 8 with a pharmaceutically acceptable carrier.
31 . A method of treating a condition in a subject in need thereof comprising administering to said subject an effective amount of at least one compound comprising formula VII:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
R 3 is any substituent;
R 4 is optionally substituted
optionally substituted
or substituted
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof.
32 . The method as recited in claim 31 wherein said condition is a MAP kinase and/or an HMG-CoA reductase-related condition.