1312430-00-4Relevant academic research and scientific papers
Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase in Vivo
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.
, p. 1660 - 1670 (2020/03/17)
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.
OXADIAZOLE DERIVATIVE HAVING ENDOTHELIAL LIPASE INHIBITORY ACTIVITY
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Page/Page column 38, (2012/10/08)
Disclosed is a compound which is useful as an endothelial lipase inhibitor. A compound represented by the formula: its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is aromatic carbocycle or aromatic heterocycle,Z is —NR5—, —O— or —S—,R5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl or the like,R1 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or the like,R2 and R3 are each independently hydrogen, halogen, hydroxy or the like,R4 is a group represented by the formula: —(CR6R7)n-R8, wherein R6 and R7 are each independently hydrogen, halogen, hydroxy or the like, n is an integer of 0 to 3, R8 is carboxy, cyano, substituted or unsubstituted alkyl or the like, Rx is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or the like,m is an integer of 0 to 3.
