Cysteine protease inhibitors and uses thereof
The invention provides for novel cysteine protease inhibitors and compositions comprising novel cysteine protease derivatives. The invention further provides for methods for treatment of neurodegenerative diseases comprising administration novel cysteine protease inhibitors or compositions comprising novel cysteine protease inhibitors. In some embodiments, the cysteine protease inhibitors are calpain inhibitors.
1. A method of treating Alzheimer's disease in a subject in need thereof comprising administration of a therapeutically effective amount of a compound having a structure of formula (I-a):
wherein,
R 1 is CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is —(CH 2 )-thiazolyl;
R 5 is —(C 1 -C 6 )-alkyl-R 6 , —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(CH 2 ) n -aryl, or
—(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen of
n is an integer from 0-4; and
p is an integer from 0-3.
2. A method of increasing long-term potentiation in a subject comprising administration of a therapeutically effective amount of a compound having a structure of formula (I-a),
wherein,
R 1 is CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is —(CH 2 )-thiazolyl;
R 5 is-(C 1 -C 6 )-alkyl-R 6 , —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(CH 2 ) n -aryl, or
(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 1 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or
n is an integer from 0-4; and
p is an integer from 0-3.
3. A method of improving memory in a subject comprising administration of a therapeutically effective amount of a compound having a structure of formula (I-a),
wherein,
R 1 is CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is —(CH 2 )-thiazolyl;
R 5 is-(C 1 -C 6 )-alkyl-R 6 , —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(CH 2 ) n -aryl, or
(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or)-N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 ,—S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or
n is an integer from 0-4; and
p is an integer from 0-3.
4. The method of claim 3 , wherein the subject has Alzheimer's Disease.
5. The method of claim 1 , wherein the compound is formulated as a pharmaceutical composition.
6. The method of claim 5 , wherein the pharmaceutical composition is formulated: as a sterile injectable solution or dispersion, for intravenous or oral administration, or for transmucosal or transdermal administration.
7. The method of claim 1 , wherein
(a) R 1 is —CO 2 H or —CO 1 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is —(CH 2 ) n -phenyl, or —(CH 2 ) n -heteroaryl, wherein said phenyl or heteroaryl are substituted with one or more R 7 groups;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, phenyl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said phenyl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or —(C 1 -C 2 )-alkyl;
n is an integer from 0-2; and
p is an integer from 0-1;
(b) R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is —(CH 2 )-triazolyl, wherein said triazolyl is substituted with an R 7 group;
R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or —(C 1 -C 2 )-alkyl;
and
p is an integer from 0-1;
(c) R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is —(CH 2 )-triazolyl, wherein said triazolyl is substituted with an R 7 group;
R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or methyl; and
p is an integer from 0-1; or
(d) R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen;
R 5 is
R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 3 )-alkynyl, NO 2 , —S(O) 2 NH 2 , or
and
p is an integer from 0-1.
8. The method of claim 1 , wherein the compound is:
(2S,3S)-3-((S)-1-(4-(4-fluorophenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-(4-(4-ethynylphenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid; or
(2S,3S)-3-((S)-1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid.
9. The method of claim 2 , wherein the compound is:
(2S,3S)-3-((S)-1-(4-(4-fluorophenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-(4-(4-ethynylphenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid; or
(2S,3S)-3-((S)-1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid.
10. The method of claim 3 , wherein the compound is:
(2S,3S)-3-((S)-1-(4-(4-fluorophenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-(4-(4-ethynylphenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid; or
(2S,3S)-3-((S)-1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid.
11. The method of claim 2 , wherein the compound is formulated as a pharmaceutical composition.
12. The method of claim 11 , wherein the pharmaceutical composition is formulated: as a sterile injectable solution or dispersion, for intravenous or oral administration, or for transmucosal or transdermal administration.
13. The method of claim 3 , wherein the compound is formulated as a pharmaceutical composition.
14. The method of claim 13 , wherein the pharmaceutical composition is formulated: as a sterile injectable solution or dispersion, for intravenous or oral administration, or for transmucosal or transdermal administration.
15. The method of claim 1 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is
R 5 is-(C 1 -C 4 )-alkyl-R 6 , —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or
n is an integer from 0-2; and
p is an integer from 0-1.
16. The method of claim 2 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is
R 5 is-(C 1 -C 4 )-alkyl-R 6 , —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or
n is an integer from 0-2; and
p is an integer from 0-1.
17. The method of claim 3 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is
R 5 is-(C 1 -C 4 )-alkyl-R 6 , —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or
R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or
n is an integer from 0-2; and
p is an integer from 0-1.