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We have identified a novel omega-hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in obese female Zucker (fa/fa) rats. ESP 55016 reduced serum non-HDL-cholesterol (non-HDL-C), triglyceride, and nonesterified fatty acid levels while increasing serum HDL-C and beta-hydroxybutyrate levels in a dose-dependent manner. ESP 55016 reduced fasting serum insulin and glucose levels while also suppressing weight gain. In primary rat hepatocytes, ESP 55016 increased the oxidation of [(14)C]palmitate in a dose- and carnitine palmitoyl transferase-I (CPT-I)-dependent manner. Furthermore, in primary rat hepatocytes and in vivo, ESP 55016 inhibited fatty acid and sterol synthesis. The "dual inhibitor" activity of ESP 55016 was unlikely attributable to the activation of the AMP-activated protein kinase (AMPK) pathway because AMPK and acetyl-CoA carboxylase (ACC) phosphorylation states as well as ACC activity were not altered by ESP 55016. Further studies indicated the conversion of ESP 55016 to a CoA derivative in vivo. ESP 55016-CoA markedly inhibited the activity of partially purified ACC. The activity of partially purified HMG-CoA reductase was not altered by the xenobiotic-CoA. These data suggest that ESP 55016-CoA favorably alters lipid metabolism in a model of diabetic dyslipidemia in part by initially inhibiting fatty acid and sterol synthesis plus enhancing the oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis.

The F1-ATPase/P2Y13 receptor pathway has been involved in the regulation of the HDL uptake liver and disposition via the reverse cholesterol transport. CT1007900 is a novel selective P2Y13 receptor agonist that has been shown to enhance the HDL uptake that results in the increased secretion of the bile acid, bile cholesterol and bile phospholipid into the gallbladder in mice. In the present study, CT1007900 has been evaluated in three different animal models of atherosclerosis. In ApoE -/- flow cessation model, the administration of the drug decreased the cholesterol concentration in atherosclerotic plaques. In a high fat diet fed ApoE -/- mouse model, the prevention of the progression of the plaque in aorta was further evaluated after 4-week treatment with CT1007900. The treated animals had significant decreases in plaque area, cholesterol content, VCAM1 expression and macrophage content. In the high fat diet fed rabbits, 4-week treatment reduced the cholesterol content by about 30% and also decreased the thickness of the plaques. The ApoA1 mRNA levels in the liver and ApoA1 protein concentration in the plasma increased in the drug-treated animals. The HDL content of the treated animals showed a very consistent pattern with a specific decrease in large HDL and an increase of the “intermediate” size HDL particles as compared to control animals. These intermediate HDL particles seem to be more efficient particles for the removal of cholesterol from atherosclerotic plaques by increasing efflux of cholesterol from the macrophages present in the lesions. The plasma samples from drug treated rabbits showed a dose-dependent increase in the cholesterol efflux in an in vitro assay using J774 cells. These results clearly demonstrate that improving functionality of HDL rather than the levels of HDL could have a positive impact on the atherosclerotic pathology. These data also support that P2Y13 receptor agonists could be useful pharmacological therapeutics for the treatment of complications due to atherosclerotic disease.

The biological activity of some long hydrocarbon keto-diols (and their phosphate esters) and acids, has been correlated with their lipohilicity. IC50 values of the hepatocyte lipid synthesis inhibition (in vitro) were used to measure biological activity; lipohilicities were calculated by employing a 3D molecular size approach implemented in a QLogP software package. Although no quantitative correlation was observed, the results of the study might be significant for in vivo application of these compounds as potential cardiovascular agents.