Compounds For Enzyme Inhibition

Abstract

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

1 . A compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1-4 substituents; 
         L is selected from C═O, C═S, and SO 2 ; 
         X is O; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent; 
         R 1 , R 2 , and R 3  are each independently selected from unsubstituted unsubstituted C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; 
         R 4  is N(R 5 )L-Z—R 6 ; 
         R 5  is selected from hydrogen; 
         R 6  is selected from Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are hydrogen. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1 , R 2 , and R 3  are independently selected from C 1-6 alkoxyalkyl, C 1-6 alkyl, aryl and C 1-6 aralkyl. 
     
     
         3 . The compound of  claim 2 , wherein R 1  and R 3  are C 1-6 alkoxyalkyl or C 1-6 alkyl; and R 2  is C 1-6  alkyl or C 1-6 aralkyl. 
     
     
         4 . The compound of  claim 2 , wherein R 1  and R 3  are isobutyl and R 2  is phenylmethyl. 
     
     
         5 . The compound of  claim 1 , wherein L is C═O or SO 2 , and R 6  is Ar—Y or heterocyclyl. 
     
     
         6 . The compound of  claim 5 , wherein each Ar is independently selected from phenyl, indolyl, benzofuranyl, naphthyl, quinolinyl, quinolonyl, thienyl, pyridyl, pyrazyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridazyl, and pyrimidyl or wherein heterocyclyl is selected from chromonyl, chromanyl, morpholino, and piperidinyl. 
     
     
         7 . The compound of  claim 6 , wherein Ar is substituted with Ar-Q-, wherein Q is selected from a direct bond, —O—, and C 1-6 alkyl. 
     
     
         8 . The compound of  claim 2 , wherein L is C═O or SO 2 , and R 6  is selected from Ar—Y and heterocycyl. 
     
     
         9 . The compound of  claim 8 , wherein R 6  is selected from chromonyl, chromanyl, morpholino, and piperidinyl. 
     
     
         10 . The compound of  claim 8 , wherein R 6  is Ar—Y and Ar is selected from phenyl, indolyl, benzofuranyl, naphthyl, quinolinyl, quinolonyl, thienyl, pyridyl, and pyrazyl. 
     
     
         11 . A compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         each Ar is independently a heteroaromatic group optionally substituted with 1-4 substituents; 
         L is C═O; 
         X is O; 
         Y is absent; 
         Z is absent; 
         R 1  and R 2  are each independently a C 1-6 alkoxyalkyl; 
         R 3  is a C 1-6 aralkyl; 
         R 4  is N(R 5 )L-Z—R 6 ; 
         R 5  is hydrogen; 
         R 6  is Ar—Y—; and 
         R 7  and R 8  are hydrogen. 
       
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for inhibiting an N-terminal nucleophile hydrolase, wherein said inhibitor inhibits a chymotrypsin-like activity of said 20S proteasome when said inhibitor is present at concentrations below about 5 μM, and does not inhibit trypsin-like activity or PGPH activity of said 20S proteasome when said inhibitor is present at concentrations below about 5 μM, comprising contacting the N-terminal nucleophile hydrolase with a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A method for the treatment of inflammation, comprising administering to a patient . a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 15 , wherein the inflammation is chronic inflammation. 
     
     
         17 . The method of  claim 16 , wherein the chronic inflammation is selected from the group consisting of COPD, psoriasis, bronchitis, emphysema, and cystic fibrosis. 
     
     
         18 . A method for inhibiting or reducing HIV infection, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A method for treating neurodegenerative disease, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 19 , wherein the neurodegenerative disease is selected from the group consisting of stroke, ischemic damage to the nervous system, neural trauma, multiple sclerosis, Guillain-Barre syndrome, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, Fisher Syndrome, HIV/AIDS dementia complex, axonomy, diabetic neuropathy, Parkinson's disease, Huntington's disease, bacterial meningitis, parasitic meningitis, fungal meningitis, viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, Lewy body dementia, frontal lobe dementia, subcortical dementias, focal cortical atrophy syndrome, metabolic-toxic dementia, dementias caused by infections, Alzheimer's disease. 
     
     
         21 . A method for Alzheimer's disease, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A method for treating muscle wasting disease, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         23 . A method for treating cancer, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         24 . A method for treating chronic infectious disease, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         25 . A method for treating a hyperproliferative condition, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 25 , wherein the hyperproliferative condition is selected from the group consisting of diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congestive heart failure, scleroderma, radiation-induced fibrosis, and lung fibrosis. 
     
     
         27 . A method for treating muscle disuse, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A method for treating an immune related condition, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method of  claim 28 , wherein the immune related condition is selected from the group consisting of allergy, asthma, organ/tissue rejection, lupus, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. 
     
     
         30 . A method for affecting the level of viral gene expression in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         31 . A method for altering the variety of antigenic peptides produced by the proteasome in an organism, comprising administering to the organism a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         32 . A method for treating an ischemic condition or reperfusion injury, comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 32 , wherein the ischemic condition or reperfusion injury is selected from the group consisting of acute coronary syndrome, arterial occlusive disease, atherosclerosis, infarctions, heart failure, pancreatitis, myocardial hypertrophy, stenosis, and restenosis. 
     
     
         34 . A method for inhibiting an N-terminal nucleophile hydrolase, wherein said inhibitor inhibits a chymotrypsin-like activity of said 20S proteasome when said inhibitor is present at concentrations below about 5 μM, and does not inhibit trypsin-like activity or PGPH activity of said 20S proteasome when said inhibitor is present at concentrations below about 5 μM, comprising contacting the N-terminal nucleophile hydrolase with a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A method for the treatment of inflammation, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method of  claim 35 , wherein the inflammation is chronic inflammation. 
     
     
         37 . The method of  claim 36 , wherein the chronic inflammation is selected from the group consisting of COPD, psoriasis, bronchitis, emphysema, and cystic fibrosis. 
     
     
         38 . A method for inhibiting or reducing HIV infection, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         39 . A method for treating neurodegenerative disease, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The method of  claim 39 , wherein the neurodegenerative disease is selected from the group consisting of stroke, ischemic damage to the nervous system, neural trauma, multiple sclerosis, Guillain-Barre syndrome, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, Fisher Syndrome, HIV/AIDS dementia complex, axonomy, diabetic neuropathy, Parkinson's disease, Huntington's disease, bacterial meningitis, parasitic meningitis, fungal meningitis, viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, Lewy body dementia, frontal lobe dementia, subcortical dementias, focal cortical atrophy syndrome, metabolic-toxic dementia, dementias caused by infections, Alzheimer's disease. 
     
     
         41 . A method for Alzheimer's disease, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         42 . A method for treating muscle wasting disease, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         43 . A method for treating cancer, comprising administering to a patient a therapeutically effective amount of a compound of claim, 11 or a pharmaceutically acceptable salt thereof. 
     
     
         44 . A method for treating chronic infectious disease, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         45 . A method for treating a hyperproliferative condition, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The method of  claim 45 , wherein the hyperproliferative condition is selected from the group consisting of diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congestive heart failure, scleroderma, radiation-induced fibrosis, and lung fibrosis. 
     
     
         47 . A method for treating muscle disuse, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         48 . A method for treating an immune related condition, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         49 . The method of  claim 48 , wherein the immune related condition is selected from the group consisting of allergy, asthma, organ/tissue rejection, lupus, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. 
     
     
         50 . A method for affecting the level of viral gene expression in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         51 . A method for altering the variety of antigenic peptides produced by the proteasome in an organism, comprising administering to the organism a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         52 . A method for treating an ischemic condition or reperfusion injury, comprising administering to a patient a therapeutically effective amount of a compound of  claim 11  or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The method of  claim 52 , wherein the ischemic condition or reperfusion injury is selected from the group consisting of acute coronary syndrome, arterial occlusive disease, atherosclerosis, infarctions, heart failure, pancreatitis, myocardial hypertrophy, stenosis, and restenosis. 
     
     
         54 . A method for inhibiting an N-terminal nucleophile hydrolase, wherein said inhibitor inhibits a chymotrypsin-like activity of said 20S proteasome when said inhibitor is present at concentrations below about 5 μM, and does not inhibit trypsin-like activity or PGPH activity of said 20S proteasome when said inhibitor is present at concentrations below about 5 μM, comprising contacting the N-terminal nucleophile hydrolase with a composition of any one of  claim 12  or  13 . 
     
     
         55 . A method for the treatment of inflammation, comprising administering to a patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         56 . The method of  claim 55 , wherein the inflammation is chronic inflammation. 
     
     
         57 . The method of  claim 56 , wherein the chronic inflammation is selected from the group consisting of COPD, psoriasis, bronchitis, emphysema, and cystic fibrosis. 
     
     
         58 . A method for inhibiting or reducing HIV infection, comprising administering to a patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         59 . A method for treating neurodegenerative disease, comprising administering to a patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         60 . The method of  claim 59 , wherein the neurodegenerative disease is selected from the group consisting of stroke, ischemic damage to the nervous system, neural trauma, multiple sclerosis, Guillain-Barre syndrome, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, Fisher Syndrome, HIV/AIDS dementia complex, axonomy, diabetic neuropathy, Parkinson's disease, Huntington's disease, bacterial meningitis, parasitic meningitis, fungal meningitis, viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, Lewy body dementia, frontal lobe dementia, subcortical dementias, focal cortical atrophy syndrome, metabolic-toxic dementia, dementias caused by infections, Alzheimer's disease. 
     
     
         61 . A method for Alzheimer's disease, comprising administering to a patient a therapeutically effective amount of a compound of a composition of any one of  claim 12  or  13 . 
     
     
         62 . A method for treating muscle wasting disease, comprising administering to a patient a therapeutically effective amount of a compound of a composition of any one of  claim 12  or  13 . 
     
     
         63 . A method for treating cancer, comprising administering to a patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         64 . A method for treating chronic infectious disease, comprising administering to a patient a therapeutically effective amount of a compound of a composition of any one of  claim 12  or  13 . 
     
     
         65 . A method for treating a hyperproliferative condition, comprising administering to a patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         66 . The method of  claim 65 , wherein the hyperproliferative condition is selected from the group consisting of diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congestive heart failure, scleroderma, radiation-induced fibrosis, and lung fibrosis. 
     
     
         67 . A method for treating muscle disuse, comprising administering to a patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         68 . A method for treating an immune related condition, comprising administering to a patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         69 . The method of  claim 68 , wherein the immune related condition is selected from the group consisting of allergy, asthma, organ/tissue rejection, lupus, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. 
     
     
         70 . A method for affecting the level of viral gene expression in a patient, comprising administering to the patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         71 . A method for altering the variety of antigenic peptides produced by the proteasome in an organism, comprising administering to the organism a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         72 . A method for treating an ischemic condition or reperfusion injury, comprising administering to a patient a therapeutically effective amount of a composition of any one of  claim 12  or  13 . 
     
     
         73 . The method of  claim 72 , wherein the ischemic condition or reperfusion injury is selected from the group consisting of acute coronary syndrome, arterial occlusive disease, atherosclerosis, infarctions, heart failure, pancreatitis, myocardial hypertrophy, stenosis, and restenosis.