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PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-06-15 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00138
Jon J. Hangeland 1 , Lynn M. Abell 1 , Leonard P. Adam 1 , Ji Jiang 1 , Todd J. Friends 1 , Lauren E. Haque 1 , James Neels 1 , Joelle M. Onorato 1 , Alice Ye A. Chen 1 , David S. Taylor 1 , Xiaohong Yin 1 , Thomas W. Harrity 1 , Michael D. Basso 1 , Richard Yang 1 , Paul G. Sleph 1 , David A. Gordon 1 , Christine S. Huang 1 , Ruth R. Wexler 1 , Heather J. Finlay 1 , R. Michael Lawrence 1
Affiliation  

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 = 41 nM, ELHDL 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, ELHDL 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.

中文翻译:

用可逆性内皮脂肪酶抑制剂观察到PK / PD断开

筛选了一小组针对内皮脂肪酶(EL)的非选择性脂肪酶抑制剂,确定了一种有效且可逆的抑制剂N-(3-(3,4-二氯苯基)丙基)-3-羟基-1-甲基-2-氧代-1 ,2-二氢吡啶-4-甲酰胺(5; EL IC 50= 61nM,EL HDL IC 50= 454nM)。甲板采矿发现了相关的命中物N-(3-(3,4-二氯苯基)丙基)-4-羟基-1-甲基-5-氧代-2,5-二氢-1 H-吡咯-3-羧酰胺(6a ; EL IC 50 = 41 nM,EL HDL IC 50= 1760 nM)。两种化合物对脂蛋白脂肪酶(LPL)具有选择性,但对肝脂肪酶(HL)具有非选择性。化合物的优化图6a使用HDL作为导致基板EL抑制ñ - (4-(3,4- -二氯-苯基)丁-2-基)-1-乙基-4-羟基-5-氧代-2,5-二氢1 H-吡咯-3-甲酰胺(7c; EL IC 50 = 148 nM,EL HDL IC 50 = 218 nM)具有比化合物6a更高的PK值,提供了一种工具分子来测试增加HDL-胆固醇(HDL- C)使用可逆EL抑制剂的体内水平。化合物7c 尽管实现了基于酶活性和蛋白质结合的血浆暴露目标,但并未增加HDL-C的体内含量,这表明需要开发更多具有生理相关性的体外测定法来指导化合物在体内的评估。
更新日期:2018-06-15
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