Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: identification of (S)-N-[1-(4-fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibition.
Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: identification of (S)-N-[1-(4-fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibition.
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氟取代可以阻断 CYP3A4 代谢依赖性抑制：将 (S)-N-[1-(4-氟-3-吗啉-4-基苯基)乙基]-3-(4-氟苯基)丙烯酰胺鉴定为口服生物可利用的 KCNQ2
DOI：
10.1021/jm034111v
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发表时间：
2003
影响因子：
7.3
通讯作者：
M. Sinz
中科院分区：
文献类型：
--
作者：
Yong;C. Davis;S. Dworetzky;W. Fitzpatrick;D. Harden;Huan He;Ronald J. Knox;Amy E. Newton;Thomas Philip;C. Polson;D. V. Sivarao;Li;S. Tertyshnikova;David Weaver;S. Yeola;M. Zoeckler;M. Sinz
(S)- n- [1-(3-morpholin-4-ylphenyl)乙基]-3-苯基丙烯酰胺观察到CYP3A4代谢依赖性抑制（MDI），发现反应性中间体的形成负责(1)。结构- 3a4 MDI关系的研究最终发现了一种双氟类似物，(S)- n-[1-（4-氟-3-morpholin-4-ylphenyl）乙基]-3-（4-氟-苯基）丙烯酰胺(2)，作为一种口服生物可利用的不含CYP3A4 MDI的KCNQ2开启剂。
The formation of a reactive intermediate was found to be responsible for CYP3A4 metabolism-dependent inhibition (MDI) observed with (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenyl-acrylamide (1). Structure-3A4 MDI relationship studies culminated in the discovery of a difluoro analogue, (S)-N-[1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl]-3-(4-fluoro-phenyl)acrylamide (2), as an orally bioavailable KCNQ2 opener free of CYP3A4 MDI.