3 research outputs found
PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor
Screening of a small set of nonselective
lipase inhibitors against
endothelial lipase (EL) identified a potent and reversible inhibitor, <i>N</i>-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide
(<b>5</b>; EL IC<sub>50</sub> = 61 nM, EL<sub>HDL</sub> IC<sub>50</sub> = 454 nM). Deck mining identified a related hit, <i>N</i>-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1<i>H</i>-pyrrole-3-carboxamide (<b>6a</b>; EL IC<sub>50</sub> = 41 nM, EL<sub>HDL</sub> IC<sub>50</sub> = 1760 nM). Both compounds
were selective against lipoprotein lipase (LPL) but nonselective versus
hepatic lipase (HL). Optimization of compound <b>6a</b> for
EL inhibition using HDL as substrate led to <i>N</i>-(4-(3,4<b>-</b>dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1<i>H</i>-pyrrole-3-carboxamide (<b>7c</b>; EL IC<sub>50</sub> = 148 nM, EL<sub>HDL</sub> IC<sub>50</sub> = 218 nM) having improved
PK over compound <b>6a</b>, providing a tool molecule to test
for the ability to increase HDL-cholesterol (HDL-C) levels in vivo
using a reversible EL inhibitor. Compound <b>7c</b> did not
increase HDL-C in vivo despite achieving plasma exposures targeted
on the basis of enzyme activity and protein binding demonstrating
the need to develop more physiologically relevant in vitro assays
to guide compound progression for in vivo evaluation