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 VI:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
R 4 is optionally substituted
and R 5 is optionally substituted aryl or heteroaryl, or a salt therof.
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 VI:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
R 4 is optionally substituted
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof,
with the proviso that when R 2 is an alkyl from 1-3 carbon atoms, trifluoromethyl, diakylamino where alkyl is 1-4 carbon atoms, pyrrolidino, piperidino, morpholino or piperazino, then R 4 is substituted.
9 . The compound as recited in claim 8 wherein R 2 is an alkyl of from one to four carbon atoms.
10 . The compound as recited in claim 8 wherein R 2 is dimethylamino.
11 . The compound as recited in claim 8 wherein R 2 is 1-methylpropyl.
12 . The compound as recited in claim 8 wherein R 2 is isopropyl.
13 . The compound as recited in claim 8 wherein R 2 is phenyl.
14 . The compound as recited in claim 8 wherein R 2 is hydrogen.
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 3-trifluoromethylphenyl.
20 . The compound as recited in claim 8 wherein R 5 is 4-fluorophenyl.
21 .- 25 . (canceled)
26 . A compound comprising formula VI:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
R 4 is substituted
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof.
27 . A compound comprising formula VIa
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,
with the proviso that when R 2 is an alkyl from 1-3 carbon atoms, trifluoromethyl, diakylamino in which alkyl is 1-4 carbon atoms, pyrrolidino, piperidino, morpholino or piperazino, then R 4 is substituted.
28 . 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 pyridinyl ring is optionally substituted;
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof,
with the proviso that when R 2 is an alkyl from 1-3 carbon atoms, trifluoromethyl, diakylamino in which alkyl is 1-4 carbon atoms, pyrrolidino, piperidino, morpholino or piperazino, then R 4 is substituted.
29 . A pharmaceutical composition comprising an effective amount of at least one compound as recited in claim 8 with a pharmaceutically acceptable carrier.
30 . 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 VI:
wherein R 1 is
n being 0 or any integer;
R 2 is optionally substituted alkyl, aryl, or heteroaryl;
R 4 is optionally substituted
and R 5 is optionally substituted aryl or heteroaryl, or a salt thereof,
with the proviso that when R 2 is an alkyl from 1-3 carbon atoms, trifluoromethyl, diakylamino where alkyl is 1-4 carbon atoms, pyrrolidino, piperidino, morpholino or piperazino, then R 4 is substituted.
31 . The method as recited in claim 30 wherein said condition is a MAP kinase and/or an HMG-CoA reductase-related condition.