By introducing particular atoms into a fatty acid, fatty acid analogues are produced that are not catabolized by β-oxidation. For example, European Patent Specification No. 0345038 described the preparation of non-β-oxidizable fatty acid analogues having the general formulaAlkyl-X—CH2COORwherein Alkyl represents a saturated or unsaturated hydrocarbon group of from 8 to 22 carbon atoms; X represents O, S, SO, and SO2; and R represents hydrogen or a C1-C4 alkyl. Subsequently, PCT/NO99/00135, PCT/NO99/00136, and PCT/NO99/00149 described similar non-β-oxidizable fatty acid analogues having the formulaCH3—[CH2]m—[Xi—CH2]n—COORwherein n is an integer from 1 to 12; m is an integer from 0 to 23; i is an odd number that indicates the position of Xi relative to COOR; Xi are independently selected from the group comprising O, S, SO, SO2, Se, and CH2; and R represents hydrogen or C1-C4 alkyl; with the proviso that at least one of the Xi is not CH2. As indicated by these two formulae, these compounds comprise one or several X groups (e.g., selenium or sulfur) at positions 3, 5, 7, 9, etc.
Due to the X atom (e.g., sulfur or selenium) that is substituted in the carbon chain of these fatty acid analogues, the compounds are not β-oxidized in the mitochondria beyond the position of the X atom. Thus, the degradation of these molecules must start from the methyl end of the fatty acid, which is a rather slow metabolic process. As such, the catabolism of these fatty acid analogues includes ω-oxidation and chain shortening of the dicarboxylic acid by peroxisomes. Enzymes in the endoplasmic reticulum ω-hydroxylate and further oxidize the hydroxylated fatty acid to a dicarboxylic acid. This acid may then be chain shortened by β-oxidation in the peroxisomes.
These substituted analogues have been demonstrated to have general antioxidant properties due to the presence of the heteroatom (see, e.g., WO/1997/03663). In addition, the biochemical characteristics of non-β-oxidizable fatty acid analogues provide particular beneficial activities, for example, to treat and/or prevent obesity (NO 2000 5461); diabetes (NO 2000 5462); primary and secondary stenosis (NO 2000 5463); cancer (NO 2002 5930); proliferate skin disorders (NO 2003 1080); and inflammatory and autoimmune disorders (NO 2003 2054). See also Int'l App. Nos. WO/1999/058123, WO/2001/NO00301, WO/2001/NO00393, and WO/2001/NO00470; U.S. Pat. Nos. 6,365,628; 6,441,036; 6,417,232; and 7,026,356; and U.S. Pat. App. Pub. No. 2002198259.
Additional work described synthetic phospholipid compounds containing non-β-oxidizable fatty acid analogues. (see, e.g., U.S. Pat. No. 8,178,713). These phospholipids (e.g., phosphatidylcholine and triacylglycerol compounds) increased fatty acid oxidation and decreased hepatic lipid levels in vivo. Due to similarities in molecular structure with the fatty acid analogues from which they are synthesized, these phospholipids are anticipated to have similar biological activities as the fatty acid analogues, e.g., as agents to treat hyperinsulinemia, hyperglycemia, fatty liver, and obesity. However, the in vitro synthesis of these lipid compounds lacks efficiency. Moreover, the synthetic phospholipid preparations may contain non-natural substances that are not desirable or appropriate for administration to a subject.