Cysteine protease inhibitors and uses thereof
AssigneesThe Trustees of Columbia University in the City of New York, The Board of Trustees of the University of Illinois
InventorsGregory R. J. Thatcher, Isaac Thomas Schiefer, Ottavio Arancio, Mauro Fa
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Abstract
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.
Claims17
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,
- R1 is CO2H or —CO2(C1-C4)-alkyl;
- R2 is hydrogen or —(C1-C4)-alkyl;
- R4 is —(CH2)-thiazolyl;
- R5 is —(C1-C6)-alkyl-R6, —(C2-C5)-alkenyl, —(C2-C5)-alkynyl, —(CH2)n-aryl, or
- —(CH2)n-heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R7 groups;
- R6 is —N(R10)C(O)R8 or —N(R10)S(O)2R8;
- R7 is independently halogen, —(C1-C3)-alkyl, aryl, methylenedioxyphenyl, or —S(O)2N(R10)2, wherein said aryl is optionally substituted with one or more R9 groups;
- R8 is-(C1-C6)-alkyl-R11 or aryl, wherein aryl is optionally substituted with one or more R9 groups;
- R9 is independently hydrogen, halogen, —(C1-C4)-alkyl, —(C1-C4)-haloalkyl, —(C2-C4)-alkynyl, CN, NO2, —S(O)2N(R10)2, or
- R10 is independently hydrogen or —(C1-C4)-alkyl;
- R11 is hydrogen of
- n is an integer from 0-4;
- and
- p is an integer from 0-3.
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,
- R1 is CO2H or —CO2(C1-C4)-alkyl;
- R2 is hydrogen or —(C1-C4)-alkyl;
- R4 is —(CH2)-thiazolyl;
- R5 is-(C1-C6)-alkyl-R6, —(C2-C5)-alkenyl, —(C2-C5)-alkynyl, —(CH2)n-aryl, or
- (CH2)n-heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R7 groups;
- R6 is —N(R10)C(O)R8 or —N(R10)S(O)1R8;
- R7 is independently halogen, —(C1-C3)-alkyl, aryl, methylenedioxyphenyl, or —S(O)2N(R10)2, wherein said aryl is optionally substituted with one or more R9 groups;
- R8 is-(C1-C6)-alkyl-R11 or aryl, wherein aryl is optionally substituted with one or more R9 groups;
- R9 is independently hydrogen, halogen, —(C1-C4)-alkyl, —(C1-C4)-haloalkyl, —(C2-C4)-alkynyl, CN, NO2, —S(O)2N(R10)2, or
- R10 is independently hydrogen or —(C1-C4)-alkyl;
- R11 is hydrogen or
- n is an integer from 0-4;
- and
- p is an integer from 0-3.
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,
- R1 is CO2H or —CO2(C1-C4)-alkyl;
- R2 is hydrogen or —(C1-C4)-alkyl;
- R4 is —(CH2)-thiazolyl;
- R5 is-(C1-C6)-alkyl-R6, —(C2-C5)-alkenyl, —(C2-C5)-alkynyl, —(CH2)n-aryl, or
- (CH2)n-heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R7 groups;
- R6 is —N(R10)C(O)R8 or)-N(R10)S(O)2R8;
- R7 is independently halogen, —(C1-C3)-alkyl, aryl, methylenedioxyphenyl, or —S(O)2N(R10)2, wherein said aryl is optionally substituted with one or more R9 groups;
- R8 is-(C1-C6)-alkyl-R11 or aryl, wherein aryl is optionally substituted with one or more R9 groups;
- R9 is independently hydrogen, halogen, —(C1-C4)-alkyl, —(C1-C4)-haloalkyl, —(C2-C4)-alkynyl, CN, NO2,—S(O)2N(R10)2, or
- R10 is independently hydrogen or —(C1-C4)-alkyl;
- R11 is hydrogen or
- n is an integer from 0-4;
- and
- p is an integer from 0-3.
Dependencies are inferred from the claim text.