Methods and compositions for treating kidney disorders

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, NR5 or sulfur;
• R is a hydrogen or C(═O)C1-C8alkyl;
• each of R1, R2 and R3 independently is a hydrogen, methyl or (CH2)m—CH3;
• R4 is NR5R6, OR5, OC(═O)R7, C(═O)OR5, C(═O)R5, halogen, 5 or 6-membered lactone, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR5R6, OR5, OC(═O)R7, C(═O)OR5, C(═O)R5, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, and C1-C8 alkoxy;
• each of R5 and R6 is independently a hydrogen or C1-C8alkyl;
• R7 is a C1-C8alkyl, OR5 or NR5R6;
• m=1-12;
• and
• n=1-12;
• or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof.

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, NR5 or sulfur;
• R is a hydrogen or C(═O)C1-C8alkyl;
• each of R1, R2 and R3 independently is a hydrogen, methyl or (CH2)m—CH3;
• R4 is NR5R6, OR5, OC(═O)R7, C(═O)OR5, C(═O)R5, halogen, 5 or 6-membered lactone, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR5R6, OR5, OC(═O)R7, C(═O)OR5, C(═O)R5, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, and C1-C8 alkoxy;
• each of R5 and R6 is independently a hydrogen or C1-C8alkyl;
• R7 is a C1-C8alkyl, OR5 or NR5R6;
• m=1-12;
• and
• n=1-12;
• or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof.

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 p47phox 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, NR5 or sulfur;
• R is a hydrogen or C(═O)C1-C8alkyl;
• each of R1, R2 and R3 independently is a hydrogen, methyl or (CH2)m—CH3;
• R4 is NR5R6, OR5, OC(═O)R7, C(═O)OR5, C(═O)R5, halogen, 5 or 6-membered lactone, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR5R6, OR5, OC(═O)R7, C(═O)OR5, C(═O)R5, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, and C1-C8 alkoxy;
• each of R5 and R6 is independently a hydrogen or C1-C8alkyl;
• R7 is a C1-C8alkyl, OR5 or NR5R6;
• m=1-12;
• and
• n=1-12;
• or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof.

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, NR5 or sulfur;
• R is a hydrogen or C(═O)C1-C8alkyl;
• each of R1, R2 and R3 independently is a hydrogen, methyl or (CH2)m—CH3;
• R4 is NR5R6, OR5, OC(═O)R7, C(═O)OR5, C(═O)R5, halogen, 5 or 6-membered lactone, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR5R6, OR5, OC(═O)R7, C(═O)OR5, C(═O)R5, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, and C1-C8 alkoxy;
• each of R5 and R6 is independently a hydrogen or C1-C8alkyl;
• R7 is a C1-C8alkyl, OR5 or NR5R6;
• m=1-12;
• and
• n=1-12;
• or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof.