Niacin Mimetics, and Methods of Use Thereof

Abstract

Disclosed are heterocyclylalkyl-substituted and heteroaralkyl-substituted pyridines, and pharmaceutically acceptable salts and prodrugs thereof, that are active against a range of mammalian therapeutic indications.

1 . A method of reducing a serum or plasma level of at least one lipid selected from the group consisting of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein (a), comprising orally administering to a human in need thereof an effective amount of a niacin analog or a pharmaceutically acceptable salt thereof, wherein said oral administration is characterized by reduced flushing and reduced hepatocellular damage, as compared to oral administration of an equimolar dose of immediate-release niacin. 
     
     
         2 . The method of  claim 1 , wherein peak concentration (C max ) for the niacin analog is 40 percent or less of C max  for the equimolar oral dose of immediate-release niacin. 
     
     
         3 . The method of  claim 1 , wherein the ratio of peak concentration to area under the curve at 24 hours (C max /AUC 0-24 ) for the niacin analog is 0.35 h −1  or less. 
     
     
         4 . The method of  claim 1 , wherein the time to peak concentration (t max ) for the niacin analog is in the range of 1 to 5 hours. 
     
     
         5 . The method of  claim 1 , wherein the niacin analog has an EC 50  for β-arrestin-mediated GPR109A function which is at least 10 times greater than the EC 50  of niacin for β-arrestin-mediated GPR109A function. 
     
     
         6 . The method of  claim 1 , wherein the niacin analog when administered orally to a human also increases a serum or plasma level of high-density lipoprotein (HDL) cholesterol. 
     
     
         7 . The method of  claim 1 , wherein said oral administration is characterized by substantially no increase in serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or both. 
     
     
         8 . The method of  claim 1 , further comprising administering to the human a statin. 
     
     
         9 . The method of  claim 8 , wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. 
     
     
         10 . (canceled) 
     
     
         11 . A pharmaceutical composition, comprising a niacin analog or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; wherein said composition is formulated for oral administration; the niacin analog when administered orally to a human reduces a serum or plasma level of at least one lipid selected from the group consisting of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein (a); and oral administration of the composition is characterized by reduced flushing and reduced hepatocellular damage, as compared to administration of an equimolar oral dose of niacin. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein peak concentration (C max ) for the niacin analog is 40 percent or less of C max  for the equimolar oral dose of niacin. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the ratio of peak concentration to area under the curve at 24 hours (C max /AUC 0-24 ) for the niacin analog is 0.35 h −1  or less. 
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein the time to peak concentration (t max ) for the niacin analog is in the range of 30 minutes to 5 hours. 
     
     
         15 . The pharmaceutical composition of  claim 11 , wherein the niacin analog has an EC 50  for β-arrestin-mediated GPR109A function which is at least 10 times greater than the EC 50  of niacin for β-arrestin-mediated GPR109A function. 
     
     
         16 . The pharmaceutical composition of  claim 11 , wherein the niacin analog when administered orally to a human also increases a serum or plasma level of high-density lipoprotein (HDL) cholesterol. 
     
     
         17 . The pharmaceutical composition of  claim 11 , wherein the niacin analog when administered orally to a human induces substantially no increase in serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or both. 
     
     
         18 . The pharmaceutical composition of  claim 11 , wherein the niacin analog when administered orally to a human induces substantially no increase in serum levels of uric acid, glucose, or both. 
     
     
         19 - 114 . (canceled) 
     
     
         115 . The pharmaceutical composition of  claim 11 , wherein the niacin analog has an EC 50  for reducing serum cholesterol, LDL and/or triglycerides which, in the average human patient population, is no more than 20 percent of the half maximal concentration of the niacin analog which would cause cutaneous vasodilation (flushing) in the average human patient population. 
     
     
         116 . The pharmaceutical composition of  claim 115 , wherein the EC 50  of the niacin analog for reducing serum cholesterol, LDL and/or triglycerides is no more than 1 percent of the half maximal concentration of the niacin analog which would cause cutaneous vasodilation (flushing) in the average human patient population. 
     
     
         117 . The pharmaceutical composition of  claim 11 , wherein the niacin analog has an EC 50  for reducing serum cholesterol, LDL and/or triglycerides which, in the average human patient population, is no more than 20 percent of the concentration of the niacin analog which would cause increases in serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) requiring discontinuation of administration of the pharmaceutical composition. 
     
     
         118 . The pharmaceutical composition of  claim 11 , wherein said niacin analog when administered once per day is effective in reducing a serum lipid without causing treatment-limiting (i) hepatotoxicity and (ii) elevations in uric acid levels or glucose levels or both, that would require such treatment to be discontinued. 
     
     
         119 . The pharmaceutical composition of  claim 11 , further comprising a statin. 
     
     
         120 . The pharmaceutical composition of  claim 119 , wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. 
     
     
         121 . (canceled) 
     
     
         122 . A method of treating hyperlipidemia, hypercholesterolemia, lipodystrophy, dyslipidemia, atherosclerosis or coronary artery disease, comprising the step of administering orally to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 11 . 
     
     
         123 . A method of treating metabolic syndrome, obesity, fatty liver disease, or diabetes, comprising the step of administering orally to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 11 . 
     
     
         124 . A method of raising serum high-density lipoprotein (HDL) levels, comprising the step of administering orally to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 11 . 
     
     
         125 . A method of lowering serum low-density lipoprotein (LDL) levels or lowering serum lipoprotein (a) levels, comprising the step of administering orally to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 11 . 
     
     
         126 . A method of treating congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, angina, pellagra, Hartnup's syndrome, carcinoid syndrome, arterial occlusive disease, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, a disorder of the peripheral and central nervous system, a hematological disease, cancer, inflammation, a respiratory disease, or a gastroenterological disease, comprising the step of administering orally to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 11 . 
     
     
         127 - 135 . (canceled)