Compositions and methods of reducing serum cholesterol and pcsk9

Abstract

A method of lowering cholesterol and/or PCSK9 levels in a subject in need thereof includes administering to the subject an ADH inhibitor, AKR inhibitor, and/or SNO-CoAR inhibitor at an amount(s) effective to reduce serum cholesterol and/or PCSK9 levels.

Having described the invention, we claim: 
     
         1 . A method of lowering serum cholesterol and/or PCSK9 levels in a subject in need thereof, the method comprising:
 administering to the subject an ADH inhibitor, AKR inhibitor, and/or SNO-CoAR inhibitor at an amount(s) effective to reduce serum cholesterol and/or PCSK9 levels.   
     
     
         2 . The method of  claim 1 , wherein the ADH inhibitor, AKR inhibitor, and/or SNO-CoAR inhibitor administered to the subject: (i) reduces total serum cholesterol by at least about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or more relative to predose level; (ii) reduces serum LDL-C at least about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, or more relative to predose level; (iii) reduces serum triglyceride at least about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% relative to predose level; and/or (iv) not reduce serum HDL-C or reduces serum HDL-C no more than about 5%, about 10%, about 20%, about 25%, about 30% relative to predose level. 
     
     
         3 . The method of  claim 1 , wherein the ADH inhibitor, AKR inhibitor, and/or SNO-CoAR inhibitor administered to the subject does not lower or do not substantially lower HDL-C levels. 
     
     
         4 . The method of  claim 1 , wherein the ADH inhibitor, AKR inhibitor, and/or SNO-CoAR inhibitor does not result in accumulation of lipids in the liver. 
     
     
         5 . The method of  claim 1 , wherein the AKR inhibitor is a selective or partially selective AKR1A1 inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the AKR1A1 inhibitor includes 2,7-Difluoro-2′H,5′H-spiro[fluorene-9,4′-imidazolidine]-2′,5′-dione and analogues thereof. 
     
     
         7 . The method of  claim 6 , wherein the imirestat analogues include compounds selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are the same or different and are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 20  aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24  alkyl-carbamoyl, arylcarbamoyl, carbamido, cyano, amino, C 1 -C 24  alkyl amino, C 5 -C 20  aryl amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, sulfonamido, imino, alkylimino, arylimino, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, sulfonamide, and combinations thereof; and pharmaceutically acceptable salts thereof. 
       
     
     
         8 . The method  claim 1 , wherein the AKR1A1 inhibitor can have a selectivity for AKR1A1 versus AKR1B1≥2 times, ≥5 times, ≥10 times, ≥20 times, ≥30 times, ≥40 times, ≥50 times or more times. 
     
     
         9 . The method of  claim 1 , wherein the subject has or is at risk of diabetes and the AKR inhibitor is a selective or partially selective AKR1B1 inhibitor. 
     
     
         10 . The method of  claim 1 , wherein a selective or partially selective AKR1A1 inhibitor is administered in combination with a selective or partially selective AKR1B1 inhibitor. 
     
     
         11 . The method of  claim 10 , wherein the AKR1B1 inhibitor can have a selectivity for AKR1B1 versus AKR1A1≥2 times, ≥5 times, ≥10 times, ≥20 times, ≥30 times, ≥40 times, ≥50 times or more times. 
     
     
         12 . A method of treating a subject having or at risk of elevated serum cholesterol levels, the method comprising:
 administering to the subject an AKR1A1 inhibitor and/or AKR1B1 inhibitor at an amount(s) effective to reduce serum cholesterol and/or PCSK9 levels in the subject.   
     
     
         13 . The method of  claim 12 , wherein the subject has or is at risk of hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, early onset coronary heart disease, type I diabetes, type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hypertriglyceridemia, hyperfattyacidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, or elevated non-HDL cholesterol, peripheral vascular disease or stroke. 
     
     
         14 . The method of  claim 12 , wherein the elevated LDL-cholesterol level is above a target level of at least about 70 mg/dL, 100 mg/dL, 130 mg/dL, 160 mg/dL, or 190 mg/dL. 
     
     
         15 . The method of  claim 12 , wherein administering the AKR1A1 inhibitor results in an LDL-cholesterol level below a target level of at least about 190 mg/dL, 160 mg/dL, 130 mg/dL, 100 mg/dL, 70 mg/dL, 50 mg/dL, or 30 mg/dL. 
     
     
         16 . The method of  claim 12 , wherein administering AKR1A1 inhibitor results in a reduction of ApoB, LDL-cholesterol, VLDL-cholesterol, non-HDL-cholesterol, liver triglyceride level, serum triglycerides, serum phospholipids, or any combination thereof. 
     
     
         17 . The method of  claim 16 , wherein at least one of the ApoB reduction, the LDL-cholesterol reduction, the, VLDL-cholesterol reduction, the non-HDL-cholesterol reduction, the liver triglyceride level reduction, the serum triglycerides reduction, or serum phospholipids reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 
     
     
         18 . The method of  claim 12 , wherein the AKR inhibitor is a selective or partially selective AKR1A1 inhibitor. 
     
     
         19 . The method of  claim 18 , wherein the AKR1A1 inhibitor includes 2,7-Difluoro-2′H,5′H-spiro[fluorene-9,4′-imidazolidine]-2′,5′-dione and analogues thereof. 
     
     
         20 . The method of  claim 18 , wherein the imirestat analogues include compounds selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are the same or different and are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 20  aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24  alkyl-carbamoyl, arylcarbamoyl, carbamido, cyano, amino, C 1 -C 24  alkyl amino, C 5 -C 20  aryl amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, sulfonamido, imino, alkylimino, arylimino, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, sulfonamide, and combinations thereof; and pharmaceutically acceptable salts thereof. 
       
     
     
         21 . The method  claim 18 , wherein the AKR1A1 inhibitor can have a selectivity for AKR1A1 versus AKR1B1≥2 times, ≥5 times, ≥10 times, ≥20 times, ≥30 times, ≥40 times, ≥50 times or more times. 
     
     
         22 . The method of  claim 12 , wherein the subject has or is at risk of diabetes and the AKR inhibitor is a selective or partially selective AKR1B1 inhibitor. 
     
     
         23 . The method of  claim 22 , wherein a selective or partially selective AKR1A1 inhibitor is administered in combination with a selective or partially selective AKR1B1 inhibitor. 
     
     
         24 . The method  claim 23 , wherein AKR1B1 inhibitor can have a selectivity for AKR1B1 versus AKR1A1≥2 times, ≥5 times, ≥10 times, ≥20 times, ≥30 times, ≥40 times, ≥50 times or more times.