Fatty acid niacin conjugates and their uses
Inventors
MILNE, JILL C. • Jirousek, Michael R. • Bemis, Jean E. • Vu, Chi B.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-8304551-B2
Publication Date
2012-11-06
Expiration Date
Abstract
The invention relates to fatty acid niacin conjugates; compositions comprising an effective amount of a fatty acid niacin conjugate; and methods for treating or preventing an metabolic disease comprising the administration of an effective amount of a fatty acid niacin conjugate.
Core Innovation
The invention relates to methods for treating a metabolic disease by administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof. The compounds are defined by selections for R1, R2, and R3; W1 and W2, including that W1 and W2 can be taken together to form an imidazolidine or piperazine group and that W1 and W2 cannot be O simultaneously; and linker L selected from —O—, —S—, —S(O)—, —S(O)2—, —S—S—, and related variants.
The method addresses metabolic disease targets selected from dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, Type 2 diabetes, diabetic nephropathy, metabolic syndrome, and cardiovascular disease associated with dyslipidemia, hypertriglyceridemia, hypercholesterolemia, or Type 2 diabetes. The document further specifies exemplary Formula I embodiments and related substituent and stereochemical selections, including named structures such as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)nicotinamide and (S)-6-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-2-(nicotinamido)hexanoic acid.
A second inventive approach is also disclosed as methods for treating metabolic disease by administering an effective amount of a molecular conjugate comprising niacin and a fatty acid selected from α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid. The conjugate is defined to comprise at least two amides, establishing the invention as both Formula I compound administration and niacin-fatty acid molecular conjugate administration, each directed to overlapping metabolic disease targets.
Claims Coverage
Two independent claims are provided: one covering administration of a Formula I compound and one covering administration of a niacin-fatty acid molecular conjugate. Each independent claim is directed to therapeutic treatment of specified metabolic diseases.
Treating metabolic disease with a Formula I compound
A method for treating a metabolic disease selected from dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, Type 2 diabetes, diabetic nephropathy, metabolic syndrome, and cardiovascular disease associated with dyslipidemia, hypertriglyceridemia, hypercholesterolemia, or Type 2 diabetes, comprising administering to a patient in need an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof.
Formula I substituent and parameter constraints
The Formula I compound is defined by selections for R1, R2, and R3; W1 and W2, including formation of an imidazolidine or piperazine group and the proviso that W1 and W2 cannot be O simultaneously; and linker L selected from —O—, —S—, —S(O)—, —S(O)2—, —S—S—, and related options, with additional parameter constraints for variables including n, o, p, q, r, s, t, v, Z, and related substituent definitions.
Treating metabolic disease with a niacin-fatty acid molecular conjugate with at least two amides
A method for treating a metabolic disease selected from dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, Type 2 diabetes, diabetic nephropathy, metabolic syndrome, and cardiovascular disease associated with dyslipidemia, hypertriglyceridemia, hypercholesterolemia, or Type 2 diabetes, comprising administering to a patient in need an effective amount of a molecular conjugate comprising niacin and a fatty acid selected from α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid, wherein the conjugate comprises at least two amides.
The claims cover treatment of specified metabolic diseases by administering either a structurally defined Formula I compound under extensive substitution and parameter constraints, or a niacin-fatty acid molecular conjugate selected from named fatty acids and containing at least two amides.
Stated Advantages
Synergistic or greater-than-additive biological activity versus niacin or fatty acids alone is asserted.
Documented Applications
In vitro biological evaluation is described, including ApoB secretion in HepG2 cells and SREBP-1c target genes.
Treating dyslipidemia.
Treating hypertriglyceridemia.
Treating hypercholesterolemia.
Treating fatty liver disease.
Treating nonalcoholic fatty liver disease (NAFLD).
Treating atherosclerosis.
Treating Type 2 diabetes.
Treating diabetic nephropathy.
Treating metabolic syndrome.
Treating cardiovascular disease associated with dyslipidemia, hypertriglyceridemia, hypercholesterolemia, or Type 2 diabetes.
Interested in licensing this patent?