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 composition comprising
(a) a compound of formula I
wherein A is a covalent bond, methylene, 1,2-oxamethylene, 1,2-ethylene, 1,2-ethynylene, 1,2-ethenylene, 1,3-propylene or 1,3-propenylene;
X comprises a lipophilic moiety;
Y is hydrogen or lower alkyl; and
Z is hydrogen or hydroxy; and
(b) a compound of formula IIa and/or a salt thereof
wherein A is a covalent bond, methylene, 1,2-oxamethylene, 1,2-ethylene, 1,2-ethynylene, 1,2-ethenylene, 1,3-propylene or 1,3-propenylene;
X comprises a lipophilic moiety;
Y is hydrogen or lower alkyl; and
Z is hydrogen or hydroxy.
2 . A composition comprising
(a) a compound of formula I
wherein A is a covalent bond, methylene, 1,2-oxamethylene, 1,2-ethylene, 1,2-ethynylene, 1,2-ethenylene, 1,3-propylene or 1,3-propenylene;
X comprises a lipophilic moiety;
Y is hydrogen or lower alkyl; and
Z is hydrogen or hydroxy; and
(b) a non-statin anti-inflammatory agent.
3 . The composition of claim 1 wherein the composition comprises a ratio of compounds represented by formulae I and IIa and/or a salt thereof ranging from about 99:1 to about 1:99.
4 . The composition of claim 1 wherein the compound of formula IIa and/or a salt thereof is atorvastatin hydroxy acid.
5 . The composition of claim 1 wherein the compound of formula IIa and/or a salt thereof is pitavastatin hydroxy acid.
6 . The composition of claim 2 wherein the composition comprises a ratio of a compound represented by formula I and a non-statin anti-inflammatory agent ranging from about 99:1 to about 1:99.
7 . The composition of claim 2 wherein the non-statin anti-inflammatory agent is indomethacin.
8 . The composition of claim 2 wherein the compound of formula I is atorvastatin lactone and the non-statin anti-inflammatory agent is indomethacin.
9 . The composition of claim 8 wherein the composition has a synergistic effect.
10 . The composition of claim 1 or 2 wherein the compound of formula I is atorvastatin lactone.
11 . The composition of claim 1 or 2 wherein the compound of formula I is pitavastatin lactone.
12 . A method of treating an inflammatory condition comprising administering to a subject an effective amount of at least one of the compositions as recited in claim 1 or 2 .
13 . A method of treating an inflammatory condition comprising administering an effective amount of a statin lactone to a subject wherein the lactone inhibits a MAP kinase and the lactone is not substantially hydrolyzed to an acid form.
14 . The method as recited in claim 12 wherein the composition inhibits HMG-CoA reductase.
15 . The method as recited in claim 12 wherein the composition inhibits a MAP kinase.
16 . The method as recited in claim 12 wherein the composition inhibits HMG-CoA reductase and a MAP kinase.
17 . The method as recited in claim 12 wherein the composition is administered as an oral formulation.
18 . The method as recited in claim 12 wherein the composition is administered as a topical formulation.
19 . The method as recited in claim 12 wherein the lipophilic moiety X of the composition comprises a lipophilic moiety of an HMG-CoA reductase inhibitor.
20 . A method of treating an inflammatory condition comprising administering to a subject an effective amount of the composition recited in claim 2 wherein the compound of formula I is atorvastatin lactone.
21 . A method of treating an inflammatory condition comprising administering to a subject an effective amount of the composition recited in claim 2 wherein the non-statin anti-inflammatory agent is indomethacin.
22 . A method of treating an inflammatory condition comprising administering to a subject an effective amount of the composition recited in claim 2 wherein the compound of formula I is atorvastatin lactone and the non-statin anti-inflammatory agent is indomethacin.
23 . The method as recited in claim 21 or 22 wherein the effect is synergistic.