Methods of Treating Atrial Fibrillation with P38 Inhibitor Compounds

1 . A method of treating atrial fibrillation, preventing arrhythmia, or preventing atrial fibrosis in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a p38 inhibitor compound and a pharmaceutically acceptable carrier, wherein said compound is of Genus Ia or a metabolite, hydrate, solvate, or prodrug thereof:

and wherein R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, alkyl substituted alkyl, alkenyl, haloalkyl, nitroalkyl, thioalkyl, hydroxyalkyl, alkoxy, phenyl, substituted phenyl, halo, hydroxyl, alkoxyalkyl, carboxy, alkoxycarbonyl, CO-uronide, CO-monosaccharide, CO-oligosaccharide, and CO— polysaccharide;

X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from the group consisting of H, halo, alkoxy, and hydroxyl;

or said compound is of Genus IV or a metabolite, hydrate, solvate, or prodrug thereof:

wherein Ar is pyridinyl or phenyl;

Z is O or S;

X 3 is H, F, Cl, OH, or OCH 3 ;

R 2 is methyl, C(═O)H, C(═O)CH 3 , C(═O)O-glucosyl, fluoromethyl, difluoromethyl, trifluoromethyl, methylmethoxyl, methylhydroxyl, or phenyl; and

R 4 is H or hydroxyl;

with the proviso that when R 2 is trifluoromethyl, Z is O, R 4 is H and Ar is phenyl, the phenyl is not solely substituted at the 4′ position by H, F, or OH.

2 . The method of claim 1 , wherein the subject is a human.

3 . (canceled)

4 . The method of claim 1 , wherein the p38 inhibitor compound exhibits an IC 50 in the range of about 100 μM to about 1000 μM for inhibition of p38 MAPK.

5 . The method of claim 1 , wherein the therapeutically effective amount produces a blood or serum or other bodily fluid concentration that is less than an IC 30 for inhibition of p38 MAPK.

6 . The method of claim 1 , wherein the therapeutically effective amount is less than 50% of an amount that causes an undesirable side effect in the subject.

7 . The method of claim 1 , wherein the therapeutically effective amount of the p38 inhibitor compound suppresses the fibrillation.

8 . The method of claim 1 , wherein the therapeutically effective amount of the p38 inhibitor compound inhibits the fibrillation.

9 . The method of claim 1 , wherein the therapeutically effective amount of the p38 inhibitor compound terminates the fibrillation.

10 . The method of claim 1 , wherein the therapeutically effective amount of the p38 inhibitor compound restores normal sinus rhythm.

11 . The method of claim 1 , wherein the p38 inhibitor compound substantially lacks hemodynamic effects.

12 . The method of claim 1 , wherein the p38 inhibitor compound is pirfenidone.

13 . The method of claim 1 , wherein the p38 inhibitor compound is selected from Compounds 1 to 23 in Table 1 as disclosed herein.

14 .- 23 . (canceled)

24 . The method of claim 1 , wherein the administering comprises orally administering the p38 inhibitor compound pharmaceutical composition.

25 . The method of claim 24 , wherein the administering comprises administering a tablet or capsule, wherein the tablet or capsule comprises the pharmaceutical composition.

26 . The method of claim 25 , wherein the administering comprises administering one or more of the tablets or capsules to the subject one or more times per day.

27 .- 33 . (canceled)

34 . The method of claim 1 , wherein the arrhythmia is atrial fibrillation.

35 .- 61 . (canceled)

62 . The method of claim 34 , wherein the subject suffers from a heart disorder.

63 .- 117 . (canceled)

118 . A pharmaceutical composition to treat or suppress atrial fibrillation comprising an effective treating or suppressing amount of a p38 inhibitor compound, wherein said compound is of Genus Ia:

wherein

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, haloalkyl, nitroalkyl, thioalkyl, hydroxyalkyl, alkoxy, phenyl, substituted phenyl, halo, hydroxyl, alkoxyalkyl, carboxy, alkoxycarbonyl, CO-uronide, CO-monosaccharide, CO-oligosaccharide, and CO— polysaccharide; and

X 1 , X 2 , X 3 , X 4 , and X 5 are independently selected from the group consisting of H, halo, alkoxy, and hydroxyl or said compound is of Genus VI:

wherein

Ar is pyridinyl or phenyl; Z is O or S; and X 3 is H, F, Cl, OH, or OCH 3 ;

R 2 is methyl, C(═O)H, C(═O)CH 3 , C(═O)O-glucosyl, fluoromethyl, difluoromethyl, trifluoromethyl, methylmethoxyl, methylhydroxyl, or phenyl; and R 4 is H or hydroxyl;

with the proviso that when R 2 is trifluoromethyl, Z is O, R 4 is H and Ar is phenyl, the phenyl is not solely substituted at the 4′ position by H, F, or OH.

119 .- 122 . (canceled)

123 . The composition of any of claim 118 , wherein the effective treating or suppressing amount of the p38 inhibitor compound suppresses, inhibits, or terminates atrial fibrillation, or restores normal sinus rhythm.

124 .- 126 . (canceled)

127 . The composition of claim 118 , wherein the p38 inhibitor compound substantially lacks hemodynamic effects.

128 .- 142 . (canceled)