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 method for the treatment of chronic inflammation, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2-6 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         2 . The method of  claim 1 , wherein the chronic inflammation is selected from the group consisting of COPD, psoriasis, bronchitis, emphysema, and cystic fibrosis. 
     
     
         3 . A method for inhibiting or reducing HIV infection, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1-4 substituents; 
         L is selected from CO═O, C═S, and SO 2 ; 
         X is selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         4 . A method for treating neurodegenerative disease, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         5 . The method of  claim 4 , 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. 
     
     
         6 . A method for Alzheimer's disease, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         7 . A method for treating muscle wasting disease, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         8 . A method for treating cancer, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         9 . A method for treating chronic infectious disease, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         10 . A method for treating a hyperproliferative condition, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         11 . The method of  claim 10 , 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. 
     
     
         12 . A method for treating muscle disuse, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         13 . A method for treating an immune related condition, comprising administering to a patient a therapeutically effective amount of a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         14 . The method of  claim 13 , 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. 
     
     
         15 . 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 having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         16 . 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 having a structure of formula (III) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         17 . A method for treating an ischemic condition or reperfusion injury, comprising administering to a patient a therapeutically effective amount of 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 selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, 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, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from OR 7 , C 2 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen and C 1-6 alkyl. 
       
     
     
         18 . The method of  claim 17 , 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.