COMPOSITIONS AND METHODS FOR AMELIORATING HYPERLIPIDEMIA
The invention provides compositions comprising a pharmaceutical compound having one or more Microsomal Triglyceride Transfer Protein (MTP) inhibitors that are covalently linked to one or more Liver Fatty Acid-Binding Protein (L-FABP) inhibitors. Also disclosed are methods for using the inventive pharmaceutical compositions in the treatment of hepatic steatosis and hyperlipidemia while avoiding the harmful side effects of steatorrhea.
1 . A pharmaceutical compound made according to the process comprising:
providing a first agent that has the ability to inhibit Microsomal Triglyceride Transfer Protein (MTP);
providing a second agent that has the ability to inhibit Liver Fatty Acid-Binding Protein (L-FABP);
covalently bonding said first agent and said second agent thereby creating said pharmaceutical compound.
2 . The pharmaceutical compound of claim 1 , wherein said covalently bonding permits said pharmaceutical compound to (a) be absorbed by the intestine intact, and (c) achieve physiological activation in the liver.
3 . The pharmaceutical compound of claim L wherein said covalently bonding comprises a bond is selected from the group consisting of carboxylic esters, phospho-esters, amities (—R—N(H)—C(O)—R′, disulfides (R—S—S—R′), sulfo-esters (R—O—S(O)—R′), sulfoxide-esters (R—O—S(O)—O—R′), peroxides (R—O—O—R′), and combinations thereof.
4 . The pharmaceutical compound of claim 1 , wherein said pharmaceutical compound is capable of inhibiting MTP and L-FABP in vivo.
5 . The pharmaceutical compound of claim 4 , wherein said pharmaceutical compound is effective in the treatment of hyperlipidemia.
6 . A method for identifying a candidate composition for the treatment of hyperlipidemia comprising:
identifying a first agent capable of inhibiting Microsomal Triglyceride Transfer Protein (MTP);
identifying a second agent capable of inhibiting Liver Fatty Acid-Binding Protein (L-FABP);
identifying the combination of said first agent and said second agent as a candidate composition for use in the treatment of hyperlipidemia.
7 . Tire method of claim 6 , wherein said combination comprises a single molecule wherein said first agent and said second agent are linked by covalent bonding.
8 . The method of claim 7 , wherein said covalently bonding permits said pharmaceutical compound to (a) be absorbed by the intestine intact, and (c) achieve physiological activation in the liver.
9 . The method of claim 7 , wherein said covalent bonding comprises a bond selected from the group consisting of carboxylic esters, phospho-esters, amides (—R—N(H)—C(O)—R′, disulfides (R—S—S—R′), sulfo-esters (R—O—S(O)—R′), sulfoxide-esters (R—O—S(O)—O—R′), peroxides (R—O—O—R′), and combinations thereof.
10 . A method for treating hyperlipidemia comprising:
administering, to a patient in need thereof, an effective amount of a composition that inhibits Microsomal Triglyceride Transfer Protein (MTP) and Liver Fatty Acid-Binding Protein (L-FABP).
11 . The method of claim 10 , wherein said composition comprises a pharmaceutical compound comprising a first agent that inhibits MTP, and a second agent that inhibits L-FABP.
12 . The method of claim 11 , wherein said first agent and said second agent are linked by covalent bonding.
13 . The method of claim 12 , wherein said covalent bonding permits said composition to (a) be absorbed by the intestine intact, and (c) achieve physiological activation in the liver.
14 . The method of claim 12 , wherein said covalent bonding comprises a bond selected from the group consisting of carboxylic esters, phospho-esters, amides (—R—N(H)—C(O)—R′, disulfides (R—S—S—R′), sulfo-esters (R—O—S(O)—R′), sulfoxide-esters (R—O—S(O)—O—R′), peroxides (R—O—O—R′), and combinations thereof.
15 . A pharmaceutical compound made according to the process comprising:
identifying a first agent capable of inhibiting Microsomal Triglyceride Transfer Protein (MTP);
identifying a second agent capable of inhibiting Liver Fatty Acid-Binding Protein (L-FABP);
forming said pharmaceutical compound by covalently bonding said first agent to said second agent.
16 . The pharmaceutical compound made according to the process of claim 1 , wherein said pharmaceutical compound is capable of (a) being absorbed by the intestine intact, and (b) achieving physiological activation in the liver
17 . The pharmaceutical compound made according to the process of claim 1 , wherein said covalently bonding comprises a bond selected from the group consisting of carboxylic esters, phospho-esters, amides (—R—N(H)—C(O)—R′, disulfides (R—S—S—R′), sulfo-esters (R—O—S(O)—R′), sulfoxide-esters (R—O—S(O)—O—R′), peroxides (R—O—O—R′), and combinations thereof.
18 . The pharmaceutical compound made according to the process of claim 1 , wherein said pharmaceutical compound is capable of inhibiting MTP and L-FABP in vivo.
19 . The pharmaceutical compound made according to the process of claim 1 , wherein said pharmaceutical compound is capable of treating hyperlipidemia.
20 . A pharmaceutical compound comprising:
a first agent that inhibits Microsomal Triglyceride Transfer Protein (MTP);
a second agent that inhibits Liver Fatty Acid-Binding Protein (L-FABP); and
a covalent bond linking said first agent and said second agent.
21 . The pharmaceutical compound of claim 20 , wherein said covalent bond permits said pharmaceutical compound to (a) be absorbed by the intestine intact, and (b) achieve physiological activation in the liver.
22 . The pharmaceutical compound of claim 20 , wherein said covalent bond comprises a bond selected from the group consisting of carboxylic esters, phospho-esters, amides (R—N(H)—C(O)—R′, disulfides (R—S—S—R′), sulfo-esters (R—O—S(O)—R′), sulfoxide-esters (R—O—S(O)—O—R′), peroxides (R—O—O—R′), and combinations thereof.
23 . The pharmaceutical compound of claim 20 , wherein said compound is effective in the treatment of hyperlipidemia.
24 . A pharmaceutical compound comprising:
a first agent that inhibits Microsomal Triglyceride Transfer Protein (MTP);
and a second agent that inhibits Liver Fatty Acid-Binding Protein (L-FABP);
wherein said first pharmaceutical active and said second pharmaceutical active are joined by covalent bonding.
25 . The pharmaceutical compound of claim 24 , wherein said first agent and said second agent are small molecules.