Methods for affecting various diseases utilizing LXR compounds

Abstract

The present invention relates to methods for elevating high density lipoprotein (HDL) plasma levels, decreasing the absorption of dietary cholesterol in the intestine, decreasing the plasma level of low density lipoprotein (LDL), and increasing the conversion of cholesterol to bile acids, utilizing LXRβ selective agonists, usually without elevating the plasma levels of triglycerides. Also provided are methods of using such agonists to treat metabolic diseases alone or in combination with other active agents. Further provided are methods for treating obesity and methods for treating the complications of obesity including type II diabetes, cardiovascular disease, hyperlipidemia, and hypertension, administering an LXRα-selective antagonist.

1 . A method for elevating the plasma level of high density lipoprotein (HDL) in a mammal, said method comprising administering to said mammal an HDL-elevating, therapeutically-effective amount of an LXRβ selective agonist.  
   
   
       2 . The method of  claim 1 , further comprising administering to said mammal an additional active agent selected from the group consisting of an antihyperlipidemic agent; a plasma HDL-raising agent; an antihypercholesterolemic agent; a cholesterol biosynthesis inhibitor; an acyl-coenzyme A: a cholesterol acyltransferase inhibitor; probucol; nicotinic acid and the salts thereof-, niacinamide; a cholesterol absorption inhibitor; a bile acid sequestrant anion exchange resin; a low density lipoprotein receptor inducer; clofibrate, fenofibrate, gemfibrizol; vitamin B 6  and the pharmaceutically acceptable salts thereof, vitamin B 12 ; an antioxidant vitamin; a beta-blocker; an angiotensin II antagonist; an angiotensin converting enzyme inhibitor; a platelet aggregation inhibitor; a platelet aggregation inhibitor; a fibrinogen receptor antagonist; aspirin; a sulfonylurea; a biguanide, a thiazolidinedione; an insulin sensitizer; a dehydroepiandrosterone; an antiglucocorticoid; a TNFα inhibitor; an α-glucosidase inhibitor; pramlintide; an insulin secretogogue; insulin; phenylpropanolamine, phentermine, diethylpropion, mazindol; fenfluramine; dexfenfluramine; phentiramine; a β 3  adrenoceptor agonist agent; sibutramine; a gastrointestinal lipase inhibitor; a leptin; neuropeptide Y; enterostatin; cholecytokinin; bombesin; amvlin; a histamine H3 receptor; a dopamine D 2  receptor; melanocyte stimulating hormone; corticotrophin releasing factor; galanin, gamma amino butyric acid (GABA) and combinations thereof.  
   
   
       3 . A method of  claim 1  for elevating the plasma level of high density lipoprotein (HDL) in a mammal, without elevating the plasma level of triglycerides, said method comprising administering to said mammal an HDL-elevating, therapeutically-effective amount of an LXRβ selective agonist.  
   
   
       4 . A method of  claim 1 , further comprising decreasing the absorption of dietary cholesterol in the intestine of a mammal, said method comprising administering to said mammal an absorption-decreasing, therapeutically-effective amount of an LXRβ selective agonist.  
   
   
       5 . A method of  claim 1 , further comprising elevating HDL-associated gene expression in a cell, said method comprising administering an LXRβ selective agonist to said cell.  
   
   
       6 . The method of  claim 5 , wherein the gene is encoded by a protein or polypeptide selected from the group consisting of ABCA1, ABCG1, CYP7A, ApoE, lipoprotein lipase, and a proinflammatory gene.  
   
   
       7 . A method of  claim 1 , further comprising decreasing the plasma level of low density lipoprotein (LDL) in a mammal, said method comprising administering to said mammal an LDL-decreasing, therapeutically-effective amount of an LXRD selective agonist.  
   
   
       8 . A method of  claim 7 , further comprising decreasing the plasma level of low-density lipoprotein (LDL) in a mammal, without elevating the plasma level of triglycerides, said method comprising administering to said mammal an LDL-decreasing, therapeutically-effective amount of an LXRβ selective agonist.  
   
   
       9 . A method of  claim 7 , further comprising lowering the plasma level of low-density lipoprotein (LDL) in a mammal by increasing the conversion of cholesterol to bile acids, said method comprising administering a cholesterol-converting, therapeutically-effective amount of an LXRβ selective agonist.  
   
   
       10 . A method of identifying an LXR selective agonist selected from the group consisting of LXR β selective agonist and LXR α selective agonist.  
   
   
       11 . A method of  claim 10 , wherein identifying an LXR β selective agonist further comprises: 
 a) selecting a candidate compound;    b) testing the candidate compound in a cell-based or biochemical assay that measures the LXRα and LXRβ agonist activity of the compound; and    c) identifying those candidate compounds which are LXRβ selective agonists as those compounds whose potency is lower for LXRβ as compared to LXRα;    and/or whose efficacy is higher for LXRβ as compared to LXRα.    
   
   
       12 . A method of  claim 11 , wherein identifying an LXRβ selective agonist further comprises: 
 a) selecting a candidate compound;    b) contacting the candidate compound with a cell expressing LXRβ only and a first reporter gene containing DNA sequences to which LXRβ binds; and also contacting the candidate compound with a cell expressing LXRα only and a second reporter gene containing DNA sequences to which LXRα binds;    c) determining if the candidate is an LXRβ agonist and/or an LXRβ agonist by examining the ability of the compound to induce transcription of the reporter gene under control of LXRβ and LXRα; and    d) identifying those candidate compounds which are LXRβ selective agonists as those compounds whose potency is lower for LXRβ as compared to LXRα;    and/or whose efficacy is higher for LXRβ as compared to LXRα.    
   
   
       13 . The method of  claim 11  wherein the LXRβ selective agonist is also an LXRα antagonist.  
   
   
       14 . A method according to  claim 1 , further comprising treating a metabolic disease in a mammal, said method comprising administering to said mammal a therapeutically-effective amount of an LXRβ selective agonist.  
   
   
       15 . The method of  claim 14  wherein said metabolic disease is selected from the group consisting of cardiovascular disease, such as atherosclerosis, diabetes, obesity, gallstone disease, syndrome X, hypertension, hypercholesterolemia, cholesterol absorption or transport disease, HDL deficiencies, and hyperlipidemia.  
   
   
       16 . The method of  claim 15  wherein the disease is atherosclerosis.  
   
   
       17 . The method of  claim 16 , further comprising administering to said mammal an additional active agent selected from the group consisting of an antihyperlipidemic agent; a plasma HDL-raising agent; antihypercholesterolemic agent; a cholesterol biosynthesis inhibitor; an acyl-coenzyme A; a cholesterol acyltransferase inhibitor; probucol; nicotinic acid and the salts thereof; niacinamide; a cholesterol absorption inhibitor; a bile acid sequestrant anion exchange resin; a low density lipoprotein receptor inducer; clofibrate, fenofibrate, gemfibrizol; vitamin B 6  and the pharmaceutically acceptable salts thereof; vitamin B 12 ; an anti-oxidant vitamin; a betablocker; an angiotensin II antagonist; an angiotensin converting enzyme inhibitor; a platelet aggregation inhibitor; a platelet aggregation inhibitor; a fibrinogen receptor antagonist; aspirin; a sulfonylurea; a biguanide, a thiazolidinedione; an insulin sensitizer; a dehydroepiandrosterone; an antiglucocorticoid; a TNFα inhibitor; an α-glucosidase inhibitor; pramlintide; an insulin secretogogue; insulin; phenylpropanolamine, phentennine, diethylpropion, mazindol; fenfluramine; dexfenfluramine; phentiramine; αβ 3  adrenoceptor agonist agent; sibutramine; a gastrointestinal lipase inhibitor; a leptin; neuropeptide Y; enterostatin; cholecytokinin; bombesin, amylin; a histamine H 3  receptor; a dopamine D 2  receptor; melanocyte stimulating hormone; corticotrophin releasing factor; galanin, gamma amino butyric acid (GABA) and combinations thereof.  
   
   
       18 . A method of  claim 14 , further comprising preventing the onset of, reducing the risk of developing, or the risk of recurrence of, a metabolic disease in a mammal, said method comprising administering to said mammal a therapeutically-effective amount of an LXRβ selective agonist.  
   
   
       19 . The method of  claim 18  wherein said metabolic disease is selected from the group consisting of cardiovascular disease, such as atherosclerosis, diabetes, obesity, gallstone disease, syndrome X, hypertension, hypercholesterolemia, cholesterol absorption or transport disease, HDL deficiencies, and hyperlipidemia.  
   
   
       20 . The method of  claim 19  wherein the disease is atherosclerosis.  
   
   
       21 . The method of  claim 20 , further comprising administering an additional active agent selected from the group consisting of a sulfonylurea; a biguanide, a thiazolidinedione; an insulin sensitizer; a dehydroepiandrosterone; an antiglucocorticoid; a TNFα inhibitor; an α-glucosidase inhibitor; pramlintide; an insulin secretogogue, insulin and combinations thereof.  
   
   
       22 . A method of  claim 1 , further comprising treating obesity in a mammal, said method comprising administering to said mammal a therapeutically-effective amount of an LXRα selective antagonist.  
   
   
       23 . A method of  claim 22 , further comprising treating the complications of obesity in a mammal including type II diabetes, cardiovascular disease, hyperlipidemia, and hypertension, said method comprising administering to said mammal a therapeutically-effective amount of an LXRα selective antagonist.  
   
   
       24 . The method of  claim 23 , further comprising administering an additional active agent selected from the group consisting of phenylpropanolamine, phentermine, diethylpropion, mazindol; fenfluramine; dexfenfluramine; phentiramine; a β 3  adrenoceptor agonist agent; sibutramine; a gastrointestinal lipase inhibitor; a leptin; neuropeptide Y; enterostatin; cholecytokinin; bombesin; amylin; a histamine H 3  receptor; a dopamine D 2  receptor; melanocyte stimulating hormone; corticotrophin releasing factor; galanin, gamma amino butyric acid (GABA) and combinations thereof.  
   
   
       25 . A method of  claim 10 , further comprising identifying an LXRα selective antagonist 
 a) selecting a candidate compound;    b) testing the candidate compound in a cell-based or biochemical assay that measures LXRα and LXRβ antagonist activity of the compound; and    d) identifying those candidate compounds which are LXRα selective antagonists as those compounds whose potency is lower for LXRα as compared to LXRβ; and/or whose efficacy as an antagonist is higher for LXRα as compared to LXRβ.    
   
   
       26 . A method of  claim 25 , wherein identifying an LXRα selective antagonist further comprises: 
 a) selecting a candidate compound;    b) contacting the candidate compound with a cell expressing LXRα only and a first reporter gene containing DNA sequences to which LXRα binds; and also contacting the candidate compound with a cell expressing LXRβ only and a second reporter gene containing DNA sequences to which LXRβ binds; and    treating both sets of cells with LXR pan-agonist to induce transcription of the reporter gene;    c) determining if the candidate is an LXRα antagonist and/or an LXRβ antagonist by examining the ability of the compound to inhibit the pan-agonist induced transcription of the reporter gene under control of LXRα and LXRβ; and    d) identifying those candidate compounds which are LXRa selective antagonists as those compounds whose potency is lower for LXRα as compared to LXRβ; and/or whose efficacy as an antagonist is higher for LXRα as compared to LXRβ.    
   
   
       27 . A method of  claim 5 , further comprising identifying an LXR selective agonist which modulates the expression of a nucleic acid encoding the LXR receptor comprising the steps of: 
 a) exposing the cells which express the nucleic acid to the LXR selective agonist;    b) determining whether the agonist modulates expression of said nucleic acid; thereby identifying an agent which modulates the expression of nucleic acid encoding the protein having the sequence of LXR receptor.    
   
   
       28 . A method of  claim 5  further comprising identifying an LXR selective agonist which modulates at least one activity of the LXR receptor, comprising the steps of: 
 a) exposing the cells which express the protein to the LXR selective agonist;    b) determining whether the agonist modulates at least one activity of said protein, thereby identifying an agonist which modulates at least one activity of LXR receptor.    
   
   
       29 . A method of  claim 28  wherein the agonist modulates an activity selected from the group consisting of reverse cholesterol transport, cholesterol to bile acid conversion, absorption of dietary cholesterol, triglyceride levels, low density lipoprotein (LDL) levels, high density lipoprotein (HDL) levels, and metabolic disorders.