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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-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC₅₀ = 148 nM, EL_HDL IC₅₀ = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c 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.

SUBMITTER: Hangeland JJ

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

REPOSITORIES: biostudies-literature

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

Hangeland Jon J JJ Abell Lynn M LM Adam Leonard P LP Jiang Ji J Friends Todd J TJ Haque Lauren E LE Neels James J Onorato Joelle M JM Chen Alice Ye A AYA Taylor David S DS Yin Xiaohong X Harrity Thomas W TW Basso Michael D MD Yang Richard R Sleph Paul G PG Gordon David A DA Huang Christine S CS Wexler Ruth R RR Finlay Heather J HJ Lawrence R Michael RM

ACS medicinal chemistry letters 20180615 7

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, ELHDL 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 = 4 ...[more]

PMID: 30034599

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Project description:Pasteurella multocida can invade and translocate through endothelial cells and result in vascular-system infection, which can cause severe economic losses in the poultry industry. Antibacterial therapy (especially florfenicol) plays an important part in controlling P. multocida infection. To preserve the effect of florfenicol, in vivo pharmacokinetic/pharmacodynamic (PK/PD) modeling of florfenicol against three P. multocida strains in duck was established. Then, the efficacy of the currently marketed dose, a rational dosage regimen for populations, and the PK/PD cutoff were predicted through Monte Carlo simulations (MCSs). The area under the concentration-time curve from 0 to 24 h/minimum inhibitory concentration (AUC0-24 h /MIC) was the optimal PK/PD parameter. The PK/PD surrogate values of florfenicol against P. multocida were similar using different organs as the PD target, but varied in different strains. For the florfenicol-sensitive strain 0825Y1, when the AUC0-24 h /MIC reached 117.54 and 108.19, florfenicol showed a bactericidal effect in the liver and lung, respectively. For the florfenicol-sensitive strain 0901J1, the corresponding value was 78.39 and 54.30, respectively. For the florfenicol-resistant strain JY160110, florfenicol could attain a maximum effect of 1 - log10 reduction in bacteria in the liver and lung when the AUC0-24 h /MIC reached 2.03 and 2.06, respectively. The PK/PD-based prediction for the population dose indicated a poor effect for the low end of the currently marketed dose (40 mg/kg body weight per day), but a robust effect for the high end of the currently marketed dose (60 mg/kg body weight per day) with a target attainment rate of 92.79% and 81.44% against P. multocida in mainland China and worldwide, respectively. The recommended dose optimized by MCSs was 52 mg/kg body weight in mainland China. The PK/PD cutoff of florfenicol against P. multocida at the low end and high end of the current daily dose (40 and 60 mg/kg body weight) and predicted daily dose in mainland China (52 mg/kg body weight) was 0.25, 4, and 0.5 μg/ml, respectively. These results suggested that more than one strain should be involved for PK/PD modeling and contributed to rational use of florfenicol in populations. We also provided fundamental data for determination of florfenicol breakpoints in poultry.

Dataset Information

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

Publications

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

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