Methods and compositions for treating kidney disorders

Abstract

The present invention provides methods for treating glomerulosclerosis such as focal segmental glomerulosclerosis (FSGS) or glomerulonephritis such as immunoglobulin A nephropathy (IgAN) by cyclohexenone compounds.

What is claimed is: 
     
         1 - 31 . (canceled) 
     
     
         32 . A pharmaceutical composition for use in the treatment of glomerulosclerosis or glomerulonephritis in a subject comprising administering to the subject an effective amount of a cyclohexenone compound having the structure: 
       
         
           
           
               
               
           
         
       
       wherein each of X and Y independently is oxygen, NR 5  or sulfur;
 R is a hydrogen or C(═O)C 1 -C 8 alkyl; 
 each of R 1 , R 2  and R 3  independently is a hydrogen, methyl or (CH 2 ) m —CH 3 ; 
 R 4  is NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , halogen, 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, C 1 -C 8  haloalkyl, and C 1 -C 8  alkoxy; 
 each of R 5  and R 6  is independently a hydrogen or C 1 -C 8 alkyl; 
 R 7  is a C 1 -C 8 alkyl, OR 5  or NR 5 R 6 ; 
 m=1-12; and 
 n=1-12; or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof. 
 
     
     
         33 . A pharmaceutical composition for use in attenuating renal dysfunction or glomerular lesions in a subject comprising administering to the subject an effective amount of a cyclohexenone compound having the structure: 
       
         
           
           
               
               
           
         
       
       wherein each of X and Y independently is oxygen, NR 5  or sulfur;
 R is a hydrogen or C(═O)C 1 -C 8 alkyl; 
 each of R 1 , R 2  and R 3  independently is a hydrogen, methyl or (CH 2 ) m —CH 3 ; 
 R 4  is NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , halogen, 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, C 1 -C 8  haloalkyl, and C 1 -C 8  alkoxy; 
 each of R 5  and R 6  is independently a hydrogen or C 1 -C 8 alkyl; 
 R 7  is a C 1 -C 8 alkyl, OR 5  or NR 5 R 6 ; 
 m=1-12; and 
 n=1-12; or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof. 
 
     
     
         34 . A pharmaceutical composition for use in (a) enhancing renal nuclear factor E2-related factor 2 (Nrf2) activity in a subject; (b) inhibiting renal NF-κB activation and/or transforming growth factor (TGF)-β1 protein expression in a subject; (c) inhibiting ROS/NO and/or p47 phox  in a subject; (d) reducing CD3 + /CD69 +  T cells in a subject; (e) reducing pro-inflammatory cytokines in a subject; (f) maintaining immunoglobulin A nephropathy (IgAN) in remission in a subject; (g) enhancing glutathione peroxidase (GPx) activity in the kidney; (h) educing renal caspase-1 protein expression and/or inhibiting renal NLRP3 activation in the kidney; (i) reducing renal NF-κB level in the kidney; or (j) inhibiting apoptosis in the kidney;
 comprising administering to the subject an effective amount of a cyclohexenone compound having the structure: 
 
       
         
           
           
               
               
           
         
         wherein each of X and Y independently is oxygen, NR 5  or sulfur; 
         R is a hydrogen or C(═O)C 1 -C 8 alkyl; 
         each of R 1 , R 2  and R 3  independently is a hydrogen, methyl or (CH 2 ) m —CH 3 ; 
         R 4  is NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , halogen, 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, C 1 -C 8  haloalkyl, and C 1 -C 8  alkoxy; 
         each of R 5  and R 6  is independently a hydrogen or C 1 -C 8 alkyl; 
         R 7  is a C 1 -C 8 alkyl, OR 5  or NR 5 R 6 ; 
         m=1-12; and 
         n=1-12; or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof. 
       
     
     
         35 . The composition of  claim 34 , wherein the pro-inflammatory cytokines comprise MCP-1, IL-6, IL-1β, IL-18, or combinations thereof. 
     
     
         36 . A pharmaceutical composition for use in protecting or preventing kidney from glomerulosclerosis and/or glomerulonephritis in a subject comprising administering to the subject an effective amount of a cyclohexenone compound having the structure 
       
         
           
           
               
               
           
         
       
       which decreases the expression levels of TGF-β1 protein and collagen I, III and IV protein accumulation in the kidney,
 wherein each of X and Y independently is oxygen, NR 5  or sulfur; 
 R is a hydrogen or C(═O)C 1 -C 8 alkyl; 
 each of R 1 , R 2  and R 3  independently is a hydrogen, methyl or (CH 2 ) m —CH 3 ; 
 R 4  is NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , halogen, 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, C 1 -C 8  haloalkyl, and C 1 -C 8  alkoxy; 
 each of R 5  and R 6  is independently a hydrogen or C 1 -C 8 alkyl; 
 R 7  is a C 1 -C 8 alkyl, OR 5  or NR 5 R 6 ; 
 m=1-12; and 
 n=1-12; or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof. 
 
     
     
         37 . The pharmaceutical composition of  claim 32  for use in the treatment of glomerulosclerosis that is focal segmental glomerulosclerosis (FSGS) wherein said compound (i) enhances Nrf2 activity and/or (ii) suppresses NF-κB-dependent inflammatory and TGF-β1-mediated fibrosis in the kidney. 
     
     
         38 . The pharmaceutical composition of  claim 32  for use in the treatment of glomerulonephritis wherein said compound (i) blocking renal NLRP3 inflammasome activation and/or (ii) inhibiting the increase in T cell activation in the subject. 
     
     
         39 . The composition of  claim 32 , wherein glomerulosclerosis is focal segmental glomerulosclerosis (FSGS) or nodular glomerulosclerosis. 
     
     
         40 . The composition of  claim 32 , wherein glomerulosclerosis is focal segmental glomerulosclerosis (FSGS). 
     
     
         41 . The composition of  claim 32 , wherein glomerulonephritis is immunoglobulin A nephropathy (IgAN). 
     
     
         42 . The composition of  claim 32 , wherein said cyclohexenone compound blocks oxidative stress. 
     
     
         43 . The composition of  claim 42 , wherein the oxidative stress is blocked by reducing TGF-β1 and extracellular matrix protein expression. 
     
     
         44 . The composition of  claim 32 , wherein the cyclohexenone compound reduces CD3 + /CD69 +  T cells or pro-inflammatory cytokines in the subject. 
     
     
         45 . The composition of  claim 44 , wherein the pro-inflammatory cytokines comprise MCP-1, IL-6, IL-1β, IL-18, or combinations thereof. 
     
     
         46 . The composition of  claim 33 , wherein said glomerular lesions comprise epithelial hyperplasia lesion (EPHL). 
     
     
         47 . The composition of  claim 32 , wherein said compound is isolated from  Antrodia camphorate.