Seladelpar, marketed under the brand name Livdelzi, is a medication recently approved by the FDA on August 14, 2024, for the treatment of primary biliary cholangitis (PBC). This approval is based on the lysine dihydrate salt form of seladelpar, offering new therapeutic options for patients suffering from this chronic liver disease. Primary biliary cholangitis is a progressive autoimmune condition where the bile ducts within the liver become inflamed, damaged, and ultimately destroyed, leading to severe liver dysfunction. By targeting the peroxisome proliferator-activated receptor delta (PPARδ), a nuclear receptor involved in lipid and glucose metabolism and present in various liver cell types, seladelpar modulates inflammatory responses and reduces bile production. CymaBay Therapeutics, the developer of seladelpar, claims that this mechanism helps decrease the bile’s toxic impact on liver cells, thereby alleviating symptoms and slowing the disease’s progression.
Originally developed by Janssen Pharmaceuticals, seladelpar was licensed to CymaBay Therapeutics in 2006, with the company later positioning it for FDA approval specifically to address PBC. Recognizing its potential, the FDA granted seladelpar Breakthrough Therapy Designation in 2019 for the treatment of early-stage PBC, a designation aimed at expediting the development and review of drugs that show substantial improvement over existing therapies for serious conditions. This year, in a significant move within the pharmaceutical sector, Gilead Sciences acquired CymaBay Therapeutics for $4.3 billion, indicating a strong investment in seladelpar’s market potential and expanding Gilead’s presence in the liver disease therapeutic area.
Shortly afterward, Gilead paid Johnson & Johnson $320 million to terminate an 18-year-old licensing agreement originally set up by CymaBay with J&J in 2006, which had given J&J a role in managing seladelpar’s patent portfolio. This strategic acquisition and the subsequent agreement resolution underscore Gilead’s commitment to leveraging seladelpar as a cornerstone in their liver disease treatment portfolio.
The synthetic approach to Seladelpar presented at the originator patents (US2007060649 and WO2005042478) can be divided into the synthesis of two main building blocks, 4 and 6. Synthesis of intermediate 6 begins with the treatment of 2-cresol (1) with NaOH in MIBK/H2O, followed by etherification with methyl chloroacetate in the presence of DMAP affording ethyl (2-methylphenoxy) acetate (2), which upon sulfonylation with ClSO3H provides ethyl (4-(chlorosulfonyl)-2-methylphenoxy) acetate (3) in 93% yield. Reduction of intermediate 3 with Sn and HCl in refluxing EtOH/dioxane leads to ethyl (2-methyl-4-sulfanylphenoxy) acetate (4) in 98% yield. Intermediate 6 is prepared by Mitsunobu reaction of 4-(trifluoromethyl) phenol (5) with (R)-glycidol in the presence of DIAD and PPh3 in THF leading to desired product in 76% yield. Ring opening reaction with 2(S)-((4-(trifluoromethyl)phenoxy)methyl) oxirane (6) by ethyl (2-methyl-4-sulfanylphenoxy)acetate (4) in the presence of TBAF in THF furnishes the corresponding secondary alcohol (7) in 85% yield. Condensation of alcohol (7) with ethyl iodide by means of NaH in THF produces seladelpar ethyl ester (8), which is subjected to ester hydrolysis with aqueous LiOH in THF to obtain seladelpar (9). Salification of intermediate (9) with L-lysine in MeOH/H2O or EtOAc/MeOH/H2O yields the target seladelpar lysine (10).
ABOUT THE AUTHOR
Rodrigo Souza – Since I started my independent career, I have pursuit the development of new technologies to guide research by innovative ideas. We have been working at Federal University of Rio de Janeiro on the establishment of continuous flow technology for active pharmaceutical ingredients (API) synthesis in Brazil, showing that is possible to reduce costs on production allowing the reduction of the final price of the medicine.
