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ID: ALA4321883

Journal: J Med Chem

Title: Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase In Vivo.

Authors: Tora G, Kim SH, Pi Z, Johnson JA, Jiang J, Phillips M, Lloyd J, Abell LM, Lu H, Locke G, Adam LP, Taylor DS, Yin X, Behnia K, Zhao L, Yang R, Basso M, Caporuscio C, Chen AY, Liu E, Kirshgessner T, Onorato JM, Ryan C, Traeger SC, Gordon D, Wexler RR, Finlay HJ.

Abstract: 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.

CiteXplore: 31990537

DOI: 10.1021/acs.jmedchem.9b01831