Influence of Various Central Moieties on the Hypolipidemic Properties of Long Hydrocarbon Chain Diols and Diacids

Abstract

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.

Phase 1, Single‐ and Multiple‐Ascending‐Dose, Food‐Effect, and East Asian Subject Studies to Assess the Pharmacokinetics, Safety, and Tolerability of Bempedoic Acid, a Selective Inhibitor of Adenosine Triphosphate Citrate Lyase

“…Similar to bempedoic acid, ESP15228 is activated by ACSVL1 in hepatocytes to a CoA thioester, where bempedoic acid-CoA was characterized in vitro as a competitive inhibitor of ATP citrate lyase with an estimated inhibitory constant of 2 μM. 9 Based on structural similarities of the CoA ester conjugates and observed changes in serum lipids after bempedoic acid and ESP15228 dosing in a preclinical Zucker rat model, 21,22 ESP15228 is hypothesized to inhibit ATP citrate lyase with similar potency to bempedoic acid. However, the contribution of ESP15228 to LDL-C lowering by bempedoic acid 180 mg/day is considered to be minimal, based on observed ESP15228 AUC tau exposures that account for approximately 18.0%-22.5% of bempedoic acid AUC tau over the 100-250-mg dose range.…”

The Disposition and Metabolism of Bempedoic Acid, a Potent Inhibitor of ATP Citrate Lyase, in Healthy Human Subjects

“…ESP15228, a keto metabolite of bempedoic acid, is activated to a CoA thioester conjugate similar to the mechanism of bempedoic acid activation (Oniciu et al, 2006). The metabolism of ESP15228 by ACSVL1 leads to the formation of ESP15228-CoA, a selective inhibitor of hepatic ATP citrate lyase activity with similar potency to bempedoic acid-CoA.…”

Bempedoic Acid and the Fraudulent Fatty Acid Family: The Gold Rush to Cardiovascular Therapies in the New Millennium

“…In 1998, a small biotechnology company, Esperion Therapeutics, started developing a series of long-chain hydrocarbons with terminal hydroxymethylene and carboxylic acid groups. The Esperion Therapeutics discovery team, led by Oniciu and Dasseux, − initiated a small-molecule program based on the concept that compounds with chains similar to those of panthotenic acid and pantetheine may replace or mimic panthotenic acid in the acetyl coenzyme A (AcCoA) synthesis and generate AcCoA mimetics or form CoA esters that instead of AcCoA could intervene in lipogenesis by obstructing it, with positive effects on lipid management (Chart , ). Medicinal chemists at Esperion synthesized ω-substituted long-chain hydrocarbon diols and diacids, dual inhibitors of the de novo synthesis of fatty acids and cholesterol in vitro, which showed an effect on HDL-C levels and other lipid parameters in animal models of dyslipidemia.…”