Synthesis of Bempedoic acid

Bempedoic acid is a drug developed by Esperion Therapeutics and approved by the FDA and the European medicines agency for the treatment of hypercholesterolemia.
.
Disease: metabolic.
Target: adenosine triphosphate citrate lyase (ACL).
Mechanism of Action: Reduces the production of cytosolic acetyl-coenzyme A (acetyl-CoA).
.
Cholesterol is an essential structural component of cell membranes in the human body and serves as a precursor for the biosynthesis of numerous compounds such as steroid hormones, cell membranes, and vitamin D. Disruption in cholesterol homeostasis due to hereditary factors or diet can lead to elevated plasma cholesterol levels that can produce fatty deposits in blood vessels, which, over time, can impede proper blood flow.
.
Bempedoic acid is a medicine that lowers low-density lipoprotein cholesterol (LDL-c; also known as ‘bad’ cholesterol). The chemical structure of the molecule resembles that of oleic acid. A convenient route for the synthesis of the molecule would involve breaking the two C–C bonds adjacent to the hydroxyl group, because that would deliver two identical fragments. However, both the carbonyl group and the alkyl halide are electrophiles. Therefore, umpolung of one of the functional groups is required. Researchers at Esperion Therapeutics made use of a ketone surrogate that was employed as the nucleophilic counterpart.
.
References:
1. J. Med. Chem. 2022, 65, 9607.
2. Org. Process Res. Dev. 2021, 25, 365.
3. Am J Cardiovasc Drugs 20, 535–548 (2020).
.
#chemistry #medicinalchemistry #organicchemistry