Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL‑C Increase In Vivo

• Published in: Journal of medicinal chemistry Vol. 63; no. 4; pp. 1660 - 1670
• Main Authors: Tora, George, Kim, Soong-Hoon, Pi, Zulan, Johnson, James A, Jiang, Ji, Phillips, Monique, Lloyd, John, Abell, Lynn M, Lu, Hao, Locke, Gregory, Adam, Leonard P, Taylor, David S, Yin, Xiaohong, Behnia, Kamelia, Zhao, Lei, Yang, Richard, Basso, Michael, Caporuscio, Christian, Chen, Alice Ye, Liu, Eddie, Kirshgessner, Todd, Onorato, Joelle M, Ryan, Carol, Traeger, Sarah C, Gordon, David, Wexler, Ruth R, Finlay, Heather J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.02.2020; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; METABOLISM; CHOLESTEROL LEVELS; DISEASE; HIGH-DENSITY-LIPOPROTEIN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01831

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.