Selective caspase inhibitors and uses thereof
The present invention relates to compounds of Formula I, IA, II, HA, III, or IHA and their pharmaceutical uses. Particular aspects of the invention relate to the use of those compounds for the selective inhibition of one or more caspases. Also described are methods where the compounds of Formula I, IA, II, IIA, III, or IIIA are used in the prevention and/or treatment of various diseases and conditions in subjects, including caspase-mediated diseases such as sepsis, myocardial infarction, ischemic stroke, spinal cord injury (SCI), traumatic brain injury (TBI) and neurodegenerative disease (e.g. multiple sclerosis (MS) and Alzheimer's, Parkinson's, and Huntington's diseases).
1. A compound of Formula I:
wherein
a is 0 or 1;
b is 0 or 1 provided that when b is 0, a is 0;
A is
1) H,
2) C 1 -C 6 alkyl,
3) aryl,
4) heteroaryl,
5) heterocyclyl,
6) R 3 —C(O)—,
7) R 3 —OC(O)—;
8) R 3 —C(O)O—, or
9) R 3 —S(O) 2 —;
P2, P3, P4 and, when present, P5 and PX, are any (D) or (L) amino acid residue;
the line “-” when located between P2, P3, P4, P5 or PX represents a peptide bond or a peptidomimetic bond;
the wavy line represents either cis or trans orientation of R 1 and R 2 ;
R 1 is
1) aryl,
2) heteroaryl,
3) heterocyclyl,
4) C 2 -C 6 alkene-R 20 ,
5) SO 2 R 5 ,
6) SO 3 R 5 ,
7) SOR 5 , 8) SONHR 5 ,
9) SO 2 NHR 5 ,
10) CN,
11) CO 2 R 5 ,
12) COR 5 ,
13) PO 3 R 5 ,
14) PO(OR 5 ) 2 , or
15) PO(OR 5 ), wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R 30 ;
R 2 is
1) R 1 ; or
2) H,
3) halogen,
4) haloalkyl,
5) C 1 -C 6 alkyl,
6) C 2 -C 6 alkene,
7) C 3 -C 7 cycloalkyl,
8) OR 9 ;
9) OCOR 6 ,
10) OCO 2 R 6 ,
11) NR 7 R 8 ,
12) NHSO 2 R 6 ,
13) NHCOR 6 ,
14) aryl,
15) heteroaryl, or
16) heterocyclyl;
R 3 is
1) C 1 -C 6 alkyl,
2) aryl,
3) heteroaryl, or
4) heterocyclyl;
R 4 is 1) H, or 2) C 1 -C 6 alkyl;
R 5 is
1) H,
2) C 1 -C 6 alkyl,
3) C 2 -C 6 alkene,
4) C 3 -C 7 cycloalkyl,
5) aryl,
6) heteroaryl,
7) heterocyclyl, or
8) any optionally protected (D) or (L) amino acid residue, or non-natural amino acid residue;
R 6 is
1) any (D) or (L) amino acid residue or non-natural amino acid residue,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl, in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 7 and R 8 are independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl, or
7) heterocyclyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 10 substituents, and the aryl, the heteroaryl and the heterocyclyl are optionally substituted with one or more R 20 substituents;
R 9 is
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl, in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 10 is independently selected from:
1) halogen,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl,
7) heterocyclyl,
8) OR 9 ,
9) S(O) m R 9 ,
10) NR 7 R 8 ,
11) COR 9 ,
12) C(O)OR 9 ,
13) OC(O)R 9 ,
14) SC(O)R 9 ,
15) CONR 7 R 8 , or
16) S(O) 2 NR 7 R 8 ;
R 20 is independently selected from:
1) halogen,
2) NO 2 ,
3) CN,
4) C 1 -C 6 alkyl,
5) haloalkyl,
6) C 3 -C 7 cycloalkyl,
7) OR 7 ,
8) NR 7 R 8 ,
9) SR 7 ,
10) aryl,
11) heteroaryl,
12) heterocyclyl,
13) SO 2 R 5 ,
14) SO 3 R 5 ,
15) SOR 5 ,
16) SONHR 5 ,
17)SO 2 NHR 5 ,
18) PO 3 R 5 ,
19) PO(OR 5 ) 2 ,
20) PO(OR 5 ),
21) COR 7 ,
22) CO 2 R 7 ,
23) S(O) m R 7 ,
24) CONR 7 R 8 , or
25) S(O) 2 NR 7 R 8 , wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R 30 ;
R 30 is
1) NO 2 ,
2) C 2 -C 6 alkene-R 20 ,
3) SO 2 R 5 ,
4) SOR 5 ,
5) SONHR 5 ,
6) SO 2 NHR 5 ,
7) CN,
8) CO 2 R 5 ,
9) COR 5 ,
10) PO 3 R 5 ,
11) PO(OR 5 ) 2 , or
12) PO(OR 5 );
or a pharmaceutically acceptable salt thereof.
2. The compound, according to claim 1 , in which A is H.
3. The compound, according to claim 1 , in which A is PhCH 2 OC(O)—.
4. The compound according to claim 1 , in which R 4 is H, CH 3 or CH 3 CH 2 .
5. The compound, according to claim 1 , in which R 4 is H.
6. The compound, according to claim 1 , in which a and b are both 0.
7. The compound, according to claim 1 , in which a is 0 and b is 1.
8. The compound, according to claim 1 , in which R 1 is in the trans or E configuration.
9. The compound, according to claim 1 , R 1 is 1) SO 2 R 5 , 2) SO 3 R 5 ; or 3) SOR 5 , wherein R 5 is C 1 -C 6 alkyl, aryl, or heterocyclyl.
10. The compound, according to claim 1 , in which R 2 is 1) H, 2) halogen, 3) haloalkyl, 4) C 1 -C 6 alkyl, or 5) C 3 -C 7 cycloalkyl.
11. The compound, according to claim 10 , in which R 2 is H or Cl.
12. A compound of Formula IA
wherein
a is 0 or 1;
b is 0 or 1 provided that when b is 0, a is 0;
A is
1) H,
2) C 1 -C 6 alkyl,
3) aryl,
4) heteroaryl,
5) heterocyclyl,
6) R 3 —OC(O)—;
7) R 3 —C(O)O—, or
8) R 3 —S(O) 2 —;
AA 2 is the (R) or (S) isomer of the amino acid Val, Leu, Pro, Met, Ala, Thr, His, Ser, Lys, or Ile;
AA 3 is Gly or the (R) or (S) isomer of the amino acid Trp, Tyr, Ala, Asp, Gln, Glu, Phe, Ser, Thr, Val, Tyr, Leu, His, or Ile; or AA 3 is phenylglycine, indanylglycine, or Ala-(2′-quinolyl);
AA 4 is the (R) or (S) isomer of the amino acid Asp, Ile, Leu, Glu, Ala, Val, Tyr, Trp, Phe, or Pro;
AA 5 , when present, is the (R) or (S) isomer of the amino acid Val or Leu;
AA x , when present, is the (R) or (S) amino acid side chain of any D or L amino acid residue or the amino acid side chain of the non-natural amino acid residue;
the wavy line represents either cis or trans orientation of R 1 and R 2 ;
R 1 is
1) aryl,
2) heteroaryl,
3) heterocyclyl,
4) C 2 -C 6 alkene-R 20 ,
5) SO 2 R 5 ,
6) SO 3 R 5 ,
7) SOR 5 ,
8) SONHR 5 ,
9) SO 2 NHR 5 ,
10) CN,
11) CO 2 R 5 ,
12) COR 5 ,
13) PO 3 R 5 ,
14) PO(OR 5 ) 2 , or
15) PO(OR 5 ), wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R 30 0;
R 2 is
1) R 1 ; or
2) H,
3) halogen,
4) haloalkyl,
5) C 1 -C 6 alkyl,
6) C 2 -C 6 alkene,
7) C 3 -C 7 cycloalkyl,
8) OR 9 ;
9) OCOR 6 ,
10) OCO 2 R 6 ,
11) NR 7 R 8 ,
12) NHSO 2 R 6 ,
13) NHCOR 6 ,
14) aryl,
15) heteroaryl, or
16) heterocyclyl;
R 3 is
1) C 1 -C 6 alkyl,
2) aryl,
3) heteroaryl, or
4) heterocyclyl;
R 4 is
1) H, or
2) C 1 -C 6 alkyl;
R 5 is
1) H,
2) C 1 -C 6 alkyl,
3) c 2 -C 6 alkene,
4) c 3 -C 7 cycloalkyl,
5) aryl,
6) heteroaryl,
7) heterocyclyl, or
8) any optionally protected (D) or (L) amino acid residue;
R 6 is
1) any (D) or (L) amino acid residue,
2) C 1 -C 6 alkyl,
3) c 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl, in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 7 and R 8 are independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl, or
7) heterocyclyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 10 substituents, and the aryl, the heteroaryl and the heterocyclyl are optionally substituted with one or more R 20 substituents;
R 9 is
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl, in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 10 is independently selected from:
1) halogen,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl,
7) heterocyclyl,
8) OR 9 ,
9) S(O) m R 9 ,
10) NR 7 R 8 ,
11) COR 5 ,
12) C(O)OR 9 ,
13) OC(O)R 9 ,
14) SC(O)R 9 ,
15) CONR 7 R 8 , or
16) S(O) 2 NR 7 R 8 ;
R 20 is independently selected from:
1) halogen,
2) NO 2 ,
3) CN,
4) C 1 -C 6 alkyl,
5) haloalkyl,
6) C 3 -C 7 cycloalkyl,
7) OR 7 ,
8) NR 7 R 8 ,
9) SR 7 ,
10) aryl,
11) heteroaryl,
12) heterocyclyl,
13) SO 2 R 5 ,
14) SO 3 R 5 ,
15) SOR 5 ,
16) SONHR 5 ,
17) SO 2 NHR 5 ,
18) PO 3 R 5 ,
19) PO(OR 5 ) 2 ,
20) PO(OR 5 ),
21) COR 7 ,
22) CO 2 R 7 ,
23) S(O) m R 7 ,
24) CONR 7 R 8 , or
25) S(O) 2 NR 7 R 8 , wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R 30 ;
R 30 is
1)NO 2 ,
2) C 2 -C 6 alkene-R 20 ,
3) SO 2 R 5 ,
4) SOR 5 ,
5) SONHR 5 ,
6) SO 2 NHR 56 ,
7) CN,
8) CO 2 R 5 ,
9) COR 5 ,
10) PO 3 R 5 ,
11) PO(OR 5 ) 2 , or
12) PO(OR 5 ); or a prodrug, or a pharmaceutically acceptable salt, or the compound is labeled with a detectable label or an affinity tag thereof.
13. The compound of claim 12 wherein the compound is a compound of Formula IIA
wherein
AA 2 is the amino acid side chain of Val, Leu, Pro, Met, Ala, Thr, His, Ser, Lys, or Ile;
AA 3 is the amino acid side chain of Trp, Tyr, Ala, Asp, Gln, Phe, Ser, Thr, Val, Tyr, Gly, Leu; or
AA 3 is phenylglycine, indanylglycine, or Ala-(2′-quinolyl);
AA 4 is the amino acid side chain of Asp or Tip; or
wherein
AA 2 is the amino acid side chain of Thr, His, Val, Trp, Ile, or Ala;
AA 3 is the amino acid side chain of Glu or AA 3 is Ala-(2′-quinolyl);
AA 4 is the amino acid side chain of Ile, Leu, Glu, Asp, Ala, Pro or Val; or
wherein
AA 2 , is the amino acid side chain of Val, Ala, Thr, or His;
AA 3 is the amino acid side chain of Glu, Gln, Asp, Ala, Gly, Thr, Val, Tip; or AA 3 is phenylglycine or indanylglycine;
AA 4 is the amino acid side chain of Tyr, Tip, Phe, or Asp; and wherein A, R 1 , R 2 and R 4 are as defined in claim 12 .
14. The compound, according to claim 12 , includes compounds of Formula IIIA
wherein
AA 2 is the amino acid side chain of Ala, Ser, Lys or Val;
AA 3 is the amino acid side chain of Val, Glu, Thr, or Gln;
AA 4 is the amino acid side chain of Asp, or Leu;
AA 5 is the amino acid side chain of Val or Leu; and wherein A, R 1 1, R 2 and R 4 are as defined in claim 12 .
15. The compound according to claim 1 , wherein said compound is selected from the group consisting of:
16. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable carriers.
17. A method for treating, or reducing the risk of developing, a caspase-related disease in a subject in need thereof, comprising administering to said subject an effective amount of a compound according to claim 1 , wherein the disease is selected from the group consisting of osteoarthritis, pancreatitis, rheumatoid arthritis, diabetes, inflammatory bowel disease, Crohn's disease, psoriasis, Graft vs host disease, organ transplant rejection, osteoporosis, sepsis, septic shock, Huntington's disease, cerebral ischemia, myocardial ischemia, multiple sclerosis, neurological damage due to stroke, ulcerative colitis, and traumatic brain injury.
18. The compound, according to claim 1 , in which the pharmaceutically acceptable salt is one that allows the compound to penetrate cells.
19. The compound of claim 1 wherein P4 is a natural or non-natural alpha or beta amino acid.
20. A pharmaceutical composition comprising a compound according to claim 12 and one or more pharmaceutically acceptable carriers.
21. A pharmaceutical composition comprising a compound according to claim 15 and one or more pharmaceutically acceptable carriers.