HETEROCYCLIC INTEGRIN AGONISTS

1 . A compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from the group consisting of phenyl and C 6 heteroaryl;

ring B is selected from the group consisting of C 5-6 heteroarylene and phenylene, each of which is unsubstituted or optionally substituted with one or two C 1-4 alkyl;

ring D is selected from the group consisting of phenyl and cyclohexyl;

V is selected from the group consisting of S and O;

U 1 is selected from C, CH, and N;

U 2 is selected from the group consisting of O, C(R 3 )(R 4 ), and NR a ;

each R 1 is independently selected from the group consisting of (CH 2 ) w COOR 1a , halogen, and C 5-6 heteroaryl, wherein C 5-6 heteroaryl is optionally substituted with (CH 2 ) w COOR 1a ;

each R 1a is independently selected from the group consisting of H and C 1-6 alkyl;

each subscript w is 0, 1, or 2;

each R 2 is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, and Rea;

each R 2a is independently selected from the group consisting of C 2-6 alkyl and C 2-6 alkoxy;

each of R 3 and R 4 is independently selected from the group consisting of H and C 1-4 alkyl;

R a is selected from the group consisting of H and C 1-4 alkyl;

subscript x is 1, 0, 2, 3, 4, or 5;

subscript y is 1, 0, or 2;

subscript z is 0, 1, 2, 3, 4, or 5; and

the dashed line represents a double bond or a single bond;

provided that when V is S, U 1 is C, U 2 is NH, the dashed line represents a double bond, ring B is furan-2,5-diyl, and (R 1 ) x -(ring A)- is 4-carboxyphenyl,

(R 2 ) z -(ring D)-(CH 2 ) y — is selected from the group consisting of 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, unsubstituted phenethyl, unsubstituted cyclohexymethyl, unsubstituted benzyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 4-fluorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 4-methylbenzyl, 3-methylbenzyl, 2-methylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 2a ) z -benzyl, and (R 2a ) z -cyclohexylmethyl, wherein subscript z is 1, 2, or 3;

provided that when V is S, U 1 is C, U 2 is NH, the dashed line represents a double bond, ring B is furan-2,5-diyl, and (R 1 ) x -(ring A)- is 4-(COOEt)phenyl,

(R 2 ) z -(ring D)-(CH 2 ) y — is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, unsubstituted phenethyl, unsubstituted cyclohexymethyl, unsubstituted benzyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 4-fluorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 4-methylbenzyl, 3-methylbenzyl, 2-methylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 2a ) z -benzyl, and (R 2a ) z -cyclohexylmethyl, wherein subscript z is 1, 2, or 3;

provided that when V is O, U 1 is C, U 2 is NH, the dashed line represents a double bond, ring B is furan-2,5-diyl, and (R 1 ) x -(ring A)- is 4-carboxyphenyl,

R 2 ) z -(ring D)-(CH 2 ) y — is selected from the group consisting of 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, unsubstituted phenethyl, unsubstituted cyclohexymethyl, 3-chlorobenzyl,=2-chlorobenzyl, 3,4-dichlorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3-methylbenzyl, 2-methylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 2a ) z -phenyl, (R 2a ) z -benzyl, and (R 2a ) z -cyclohexylmethyl, wherein subscript z is 1, 2, or 3; and

provided that when V is O, U 1 is C, U 2 is S, the dashed line represents a double bond, ring B is furan-2,5-diyl, and (R 1 ) x -(ring A)- is 4-(COOMe)phenyl or 4-(COOEt)phenyl,

R 2 ) z -(ring D)-(CH 2 ) y — is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, unsubstituted phenethyl, unsubstituted cyclohexymethyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3 -methoxybenzyl, 2-methoxybenzyl, 4-methylbenzyl, 3-methylbenzyl, 2-methylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 2a ) z -phenyl, (R 2a ) z -benzyl, and (R 2a ) z -cyclohexylmethyl, wherein subscript z is 1, 2, or 3.

2 . The compound of claim 1 , having a structure according to Formula II

or a pharmaceutically acceptable salt thereof, wherein

R 1 is COOR 1a , wherein R 1a is selected from the group consisting of H and C 1-6 alkyl; and

each R 2 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

3 . The compound of claim 2 , wherein subscript z is 0, 1, 2, or 3.

4 . The compound of claim 2 , wherein ring B is selected from the group consisting of meta-phenylene; thiophene-2,5-diyl; pyridine-2,6-diyl; pyrimidine-2,4-diyl; and furan-2,5-diyl.

5 . The compound of claim 2 , wherein ring A is selected from the group consisting of phenyl, pyridin-2-yl, and pyridin-3-yl.

6 . The compound of claim 5 , wherein R 1a is selected from the group consisting of COOH and COOMe.

7 . The compound of claim 2 , selected from the group consisting of

and pharmaceutically acceptable salts thereof.

8 . The compound of claim 1 , having a structure according to Formula III

or a pharmaceutically acceptable salt thereof, wherein

R 1 is COOR 1a , wherein R 1a is selected from the group consisting of H and C 1-6 alkyl; and

each R 2 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

9 . The compound of claim 8 , wherein subscript z is 0, 1, 2, or 3.

10 . The compound of claim 8 , wherein ring B is selected from the group consisting of meta-phenylene; thiophene-2,5-diyl; pyridine-2,6-diyl; pyrimidine-2,4-diyl; and furan-2,5-diyl.

11 . The compound of claim 8 , having a structure according to Formula IIIa

or a pharmaceutically acceptable salt thereof, wherein

R 1 is COOR 1a , wherein R 1a is selected from the group consisting of H and C 1-6 alkyl; and

each R 2 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

12 . The compound of claim 11 , wherein subscript z is 0, 1, 2, or 3.

13 . The compound of claim 8 , having a structure according to Formula IIIb

or a pharmaceutically acceptable salt thereof, wherein

R 1 is COOR 1a , wherein R 1a is selected from the group consisting of H and C 1-6 alkyl; and

each R 2 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

14 . The compound of claim 13 , wherein subscript x is 1 or 2 and subscript z is 0, 1, 2, or 3.

15 . The compound of claim 8 , wherein ring A is selected from the group consisting of phenyl, pyridin-2-yl, and pyridin-3-yl.

16 . The compound of claim 15 , wherein R 1a is selected from the group consisting of COOH and COOMe.

17 . The compound of claim 8 , selected from the group consisting of

and pharmaceutically acceptable salts thereof.

18 . The compound of claim 1 , having a structure according to Formula IV

or a pharmaceutically acceptable salt thereof, wherein

R 1 is COOR 1a , wherein R 1a is selected from the group consisting of H and C 1-6 alkyl; and

each R 2 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

19 . The compound of claim 18 , wherein subscript x is 1 or 2 and subscript z is 0, 1, 2, or 3.

20 . The compound of claim 18 , wherein ring B is selected from the group consisting of meta-phenylene; thiophene-2,5-diyl; pyridine-2,6-diyl; pyrimidine-2,4-diyl; and furan-2,5-diyl.

21 . The compound of claim 18 , wherein ring A is selected from the group consisting of phenyl, pyridin-2-yl, and pyridin-3-yl.

22 . The compound of claim 21 , wherein R 1a is selected from the group consisting of COOH and COOMe.

23 . The compound of claim 18 , selected from the group consisting of

and pharmaceutically acceptable salts thereof.

24 . A compound according to Formula XI:

or a pharmaceutically acceptable salt thereof, wherein:

ring A 1 is C 6 heteroaryl;

ring B 1 is selected from the group consisting of phenylene and C 5-6 heteroarylene, each of which is optionally substituted with one or two C 1-4 alkyl;

ring D 1 is selected from the group consisting of cyclohexyl and phenyl;

V 1 is selected from the group consisting of O and S;

each R 11 is independently selected from the group consisting of halogen and (CH 2 ) s COOR 11a ,

provided that at least one R 11 is other than halogen;

each R 11a is independently selected from the group consisting of H and C 1-6 alkyl;

each subscript s is 0, 1, or 2;

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, and R 12a ;

each R 12a is independently selected from the group consisting of C 2-6 alkyl and C 2-6 alkoxy;

subscript t is 0, 1, 2, 3, 4, or 5;

subscript u is 0, 1, or 2; and

subscript v is 0, 1, 2, 3, 4, or 5.

25 . The compound of claim 24 , wherein subscript t is 1 or 2 and subscript v is 0, 1, 2, or 3.

26 . The compound of claim 24 , having a structure according to Formula XIIa

or a pharmaceutically acceptable salt thereof, wherein

R 11 is COOR 11a ;

R 11a is selected from the group consisting of H and C 1-6 alkyl;

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy; and

Y 11 , Y 12 , and Y 13 are independently selected from the group consisting of CH and N.

27 . The compound of claim 26 , wherein subscript v is 0, 1, 2, or 3.

28 . The compound of claim 26 , wherein Y 11 , Y 12 , and Y 13 are CH.

29 . The compound of claim 26 , wherein Y 11 is N, and wherein Y 12 and Y 13 are CH.

30 . The compound of claim 26 , wherein Y 11 and Y 12 are N, and wherein Y 13 is CH.

31 . The compound of claim 26 , wherein R 11a is selected from the group consisting of COOH and COOMe.

32 . The compound of claim 24 , having a structure according to Formula XIIb

or a pharmaceutically acceptable salt thereof, wherein

R 11 is COOR 11a ;

R 11a is selected from the group consisting of H and C 1-6 alkyl; and

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

33 . The compound of claim 32 , wherein subscript v is 0, 1, 2, or 3.

34 . The compound of claim 32 , wherein ring A 1 is selected from the group consisting of pyridin-2-yl and pyridin-3-yl.

35 . The compound of claim 24 , having a structure according to Formula XIIc

or a pharmaceutically acceptable salt thereof, wherein

R 11 is COOR 11a ;

R 11a is selected from the group consisting of H and C 1-6 alkyl; and

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

36 . The compound of claim 35 , wherein subscript v is 0, 1, 2, or 3.

37 . The compound of claim 35 , wherein ring A 1 is selected from the group consisting of pyridin-2-yl and pyridin-3-yl.

38 . The compound of claim 35 , wherein R 11a is selected from the group consisting of COOH and COOMe.

39 . The compound of claim 35 , selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

40 . The compound of claim 24 , having a structure according to Formula XIId

or a pharmaceutically acceptable salt thereof, wherein

R 11 is COOR 11a ;

R 11a is selected from the group consisting of H and C 1-6 alkyl; and

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

41 . The compound of claim 40 , wherein subscript v is 0, 1, 2, or 3.

42 . The compound of claim 40 , wherein ring A 1 is selected from the group consisting of pyridin-2-yl and pyridin-3-yl.

43 . A compound according to Formula XIII:

or a pharmaceutically acceptable salt thereof, wherein:

ring B 1 is selected from the group consisting of phenylene and C 5-6 heteroarylene, each of which is optionally substituted with one or two C 1-4 alkyl;

ring D 1 is selected from the group consisting of cyclohexyl and phenyl;

V 1 is selected from the group consisting of O and S;

each R″ is independently selected from the group consisting of halogen, (CH 2 ) s COOR 11a , and C 5-6 heteroaryl, wherein C 5-6 heteroaryl is optionally substituted with (CH 2 ) s COOR 11a ,

provided that at least one R 11 is other than halogen;

each R 11a is independently selected from the group consisting of H and C 1-6 alkyl;

each subscript s is 0, 1, or 2;

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, and R 12a ;

each R 12a is independently selected from the group consisting of C 2-6 alkyl and C 2-6 alkoxy;

subscript t is 0, 1, 2, 3, 4, or 5;

subscript u is 0, 1, or 2; and

subscript v is 0, 1, 2, 3, 4, or 5;

provided that when V 1 is O, ring B 1 is phen-1,5-diyl, R 11 is 4-carboxy, and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH2) u — is other than 4-methoxybenzyl;

provided that when V 1 is S, ring B 1 is thiophen-2,5-diyl, R 11 is 4-(COOMe), and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is other than 3,4,5-trimethoxybenzyl;

provided that when V 1 is S, ring B i is furan-2,5-diyl, R 11 is 4-carboxy, and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is selected from the group consisting of unsubstituted cyclohexymethyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 4-fluorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3-methylbenzyl, 2-methylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 12a ) v -phenyl, (R 12a ) v -benzyl, and (R 12a ) v -cyclohexylmethyl, wherein subscript v is 1, 2, or 3;

provided that when V 1 is S, ring B 1 is furan-2,5-diyl, R 11 is 4-(COOMe), and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, unsubstituted cyclohexymethyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 4-fluorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3-methylbenzyl, 2-methylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 12a ) z -phenyl, (R 12a ) v -benzyl, and (R 12a ) v -cyclohexylmethyl, wherein subscript v is 1, 2, or 3;

provided that when V 1 is S, ring B 1 is furan-2,5-diyl, R 11 is 4-(COOEt), and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is selected from the group consisting of unsubstituted cyclohexymethyl, 4-chlorobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, 4-isopropylbenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 2-methylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 12a ) v -phenyl, (R 12a ) v -benzyl, and (R 12a ) v -cyclohexylmethyl, wherein subscript v is 1, 2, or 3;

provided that when V 1 is S, ring B 1 is furan-2,5-diyl, R 11 is 4-(COOnBu), and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is selected from the group consisting of unsubstituted phenethyl, unsubstituted cyclohexymethyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 4-fluorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 4-methylbenzyl, 3-methylbenzyl, 2-methylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 12a ) u -phenyl, (R 12a ) u -benzyl, and (R 12a ) u -cyclohexylmethyl, wherein subscript u is 1, 2, or 3;

provided that when V 1 is O, ring B 1 is furan-2,5-diyl, R 11 is 4-carboxy, and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is selected from the group consisting of 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, unsubstituted phenethyl, unsubstituted cyclohexymethyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 12a ) u -phenyl, (R 12a ) u -benzyl, and (R 12a ) u -cyclohexylmethyl, wherein subscript u is 1, 2, or 3;

provided that when V 1 is O, ring B 1 is furan-2,5-diyl, R 11 is 4-(COOMe), and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, unsubstituted phenethyl, unsubstituted cyclohexymethyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 12a ) u -phenyl, (R 12a ) u -benzyl, and (R 12a ) u -cyclohexylmethyl, wherein subscript u is 1, 2, or 3;

provided that when V 1 is O, ring B 1 is furan-2,5-diyl, is 4-(COOEt), and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is selected from the group consisting of 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, unsubstituted phenethyl, unsubstituted cyclohexymethyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 12a ) u -phenyl, (R 12a ) u -benzyl, and (R 12a ) u -cyclohexylmethyl, wherein subscript u is 1, 2, or 3;

provided that when V 1 is O, ring B 1 is furan-2,5-diyl, R 11 is 4-(COOnBu), and subscript t is 1,

(R 12 ) v -(ring D 1 )-(CH 2 ) u — is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, unsubstituted phenethyl, unsubstituted cyclohexymethyl, 4-isopropylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, (R 12a ) u -phenyl, (R 12a ) u -benzyl, and (R 12a ) u -cyclohexylmethyl, wherein subscript u is 1, 2, or 3.

44 . The compound of claim 43 , having a structure according to Formula XIVa

or a pharmaceutically acceptable salt thereof, wherein

R 11 is COOR 11a ;

R 11a is selected from the group consisting of H and C 1-6 alkyl;

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy; and

Y 11 , Y 12 , and Y 13 are independently selected from the group consisting of CH and N.

45 . The compound of claim 44 , wherein subscript v is 0, 1, 2, or 3.

46 . The compound of claim 44 , wherein Y 11 , Y 12 , and Y 13 are CH.

47 . The compound of claim 44 , wherein Y 11 is N, and wherein Y 12 and Y 13 are CH.

48 . The compound of claim 44 , wherein Y 11 and Y 12 are N, and wherein Y 13 is CH.

49 . The compound of claim 44 , wherein R 11a is selected from the group consisting of COOH and COOMe.

50 . The compound of claim 43 , selected from the group consisting of

and pharmaceutically acceptable salts thereof.

51 . The compound of claim 43 , selected from the group consisting of

and pharmaceutically acceptable salts thereof.

52 . The compound of claim 43 , having a structure according to Formula XIVb

or a pharmaceutically acceptable salt thereof, wherein

R 11 is COOR 11a ;

R 11a is selected from the group consisting of H and C 1-6 alkyl; and

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

53 . The compound of claim 52 , wherein subscript v is 0, 1, 2, or 3.

54 . The compound of claim 52 , which is

or a pharmaceutically acceptable salt thereof.

55 . The compound of claim 43 , having a structure according to Formula XIVc

or a pharmaceutically acceptable salt thereof, wherein

R 11 is COOR 11a ;

R 11a is selected from the group consisting of H and C 1-6 alkyl; and

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

56 . The compound of claim 55 , wherein subscript v is 0, 1, 2, or 3.

57 . The compound of claim 55 , wherein R 11a is selected from the group consisting of COOH and COOMe.

58 . The compound of claim 55 , selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

59 . The compound of claim 55 , having the structure

and pharmaceutically acceptable salts thereof.

60 . The compound of claim 43 , having a structure according to Formula XIVd

or a pharmaceutically acceptable salt thereof, wherein R 11 is COOR 11a ;

R 11a is selected from the group consisting of H and C 1-6 alkyl; and

each R 12 is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.

61 . The compound of claim 60 , wherein subscript v is 0, 1, 2, or 3.

62 . A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 , 24 , and 43 or a pharmaceutically acceptable salt thereof.

63 . A method for treating a β2 integrin-mediated condition comprising administering to a patient in need thereof a compound according to any one of claims 1 , 24 , and 43 or a pharmaceutically acceptable salt thereof.

64 . The method of claim 63 , wherein the integrin-mediated condition is selected from the group consisting of acute inflammation, chronic inflammation, chronic kidney disease, neointimal thickening associated with vascular injury, atherosclerosis, tissue injury, peritonitis, diabetic nephropathy, an autoimmune disease, a neurological condition, lupus, cancer, pain, glaucoma, graft versus host disease, macular degeneration, and uveitis.