PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor.

ABSTRACT: Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC₅₀ = 61 nM, EL_HDL IC₅₀ = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC₅₀ = 41 nM, EL_HDL IC₅₀ = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl

SUBMITTER: Hangeland JJ 

PROVIDER: S-EPMC6047032 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature