Effect of 3-thiadicarboxylic acid on lipid metabolism in experimental nephrosis.

Abstract

The effect of the sulfur-substituted fatty acid analogue 1,10 6i?(carboxymethylthio)decane, also known as 3-thiadicarboxylic acid, on puromycin aminonucleoside-induced nephrotic hyperlipidemia was studied in rats. Treatment with 3-thiadicarboxylic acid (250 mg/kg) for 5 days reduced plasma levels of triglycerides from 5.8 to 2.7 mmol/L and cholesterol from 11.0 to 7.7 mmol/L. This was accounted for by decreases in very-low-density lipoprotein triglycerides, very-low-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, without any major changes in the composition of plasma lipoproteins. The activities of two enzymes involved in fatty acid synthesis (ATP:citrate lyase and fatty acid synthetase) were inhibited by 3-thiadicarboxylic acid treatment, whereas acetyl-coenzyme A carboxylase activity was unchanged. In contrast, treatment with the sulfur-substituted fatty acid analogue induced the peroxisomal /3-oxidation of fatty acids ninefold and the mitochondrial /3-oxidation by 54% to 73%, depending on the substrate used. This was accompanied by a 26% reduction in hepatic triglyceride secretion rate. The hepatic phosphatidate phosphohydrolase activity was unchanged.

Lipogenesis inhibitors: therapeutic opportunities and challenges

“…A similar dicarboxylic acid, 3-thiadicarboxylic acid, was synthesized by replacing the dimethyl substitution in the β-position with a sulfur atom. This molecule inhibited ACLY and FAS, resulting in reduced levels of plasma triglycerides and cholesterol 165 . However, neither molecule advanced beyond preclinical studies.…”

ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism

“…A similar dicarboxylic acid, 3-thiadicarboxylic acid (1,10 bis(carboxymethylthio)decane, compound 19 in Figure 6), in which the geminal dimethyl substitution in β position was replaced by a sulphur atom, reduced plasma levels of triglycerides and cholesterol in a nephrotic hyperlipidemic animal model, due to its inhibitory activity on ACLY, and on the enzymes fatty acid synthase and HMG-CoA reductase [96,97]. Esperion Therapeutics, Inc. company developed compound ETC-1002 also named bempedoic acid (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, compound 20 in Figure 7) as a therapeutic agent for patients with elevated low-density lipoprotein cholesterol (LDL-C).…”

Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery

“…134 An analogue of MEDICA16 was found in which the dimethyl group at the β-position was replaced by a sulfur atom to give 3-thiadicarboxylic acid (compound 22, Figure 10). 135 22 was able to inhibit ACLY and FASN, reducing plasma triglyceride and cholesterol levels. However, both compounds are only in preclinical studies.…”