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A series of cycloalkyl-substituted oxo-alkanedicarboxylic acids have been prepared by the TosMIC methodology departing from haloalkyl-substituted cycloalkylcarboxylic esters. cyclopropyl derivatives showed IC50 activity in the 0.3–1.0 μM range on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes, and they showed lipid-regulating properties when tested in vivo in female obese Zucker fatty rats.

Keto-substituted hydrocarbons with 11-19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g, 14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f, 14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 1 g dose-dependently modified non-HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2-3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.

Long hydrocarbon chain ethers with bis-terminal hydroxyl or carboxyl groups have been synthesized and evaluated for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in female obese Zucker fatty rats following 1 and 2 weeks of daily oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ether functionality and the gem dimethyl or methyl/aryl substituents. Biological activity was found to be greatest for tetramethyl-substituted ether diols (e.g., 28 and 31), while bis(arylmethyl) derivatives (e.g., 10, 11, and 27), diethers (e.g., 49, 50, and 56), and diphenyl ethers (e.g., 35 and 36) were the least active. For the most biologically active compound 28, we observed as much as a 346% increase in serum HDL-cholesterol and a 71% reduction in serum triglycerides at the highest dose administered (100 mg/kg) after 2 weeks of treatment. For compound 31 we observed a 69% reduction in non-HDL-cholesterol, accompanied by a 131% increase in HDL-cholesterol and an 84% reduction in serum triglycerides under the same treatment conditions.

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.

A series of long (11-15) hydrocarbon chain diols and diacids with various central functional groups and terminal gem-dimethyl or -methyl/aryl substituents was synthesized and evaluated in both in vivo and in vitro assays for its potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes, as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats, Crl:(ZUC)-faBR. The most active compounds were hydroxyl-substituted symmetrical diacids and diols with a 13-atom chain and terminal gem-dimethyl substituents. Furthermore, biological activity was enhanced by central substitution with O, C=O, S, S=O compared to the methylene analogues and was diminished for compounds with central functional groups such as carbamate, ester, urea, acetylmethylene, and hydroxymethylene.