3I28

Crystal Structure of soluble epoxide Hydrolase

3I28 の概要

• エントリーDOI: 10.2210/pdb3i28/pdb
• 関連するPDBエントリー: 3I1Y
• 分子名称: Epoxide hydrolase 2, 4-cyano-N-{(3S)-3-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]propyl}benzamide (3 entities in total)
• 機能のキーワード: hydrolase, aromatic hydrocarbons catabolism, detoxification, magnesium, metal-binding, peroxisome
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P34913
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 63122.12

構造登録者

Farrow, N.A. (登録日: 2009-06-29, 公開日: 2009-10-13, 最終更新日: 2024-02-21)

主引用文献

Eldrup, A.B.,Soleymanzadeh, F.,Taylor, S.J.,Muegge, I.,Farrow, N.A.,Joseph, D.,McKellop, K.,Man, C.C.,Kukulka, A.,De Lombaert, S.
Structure-based optimization of arylamides as inhibitors of soluble epoxide hydrolase.
J.Med.Chem., 52:5880-5895, 2009

PubMed Abstract: Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection. The screen identified N-(3,3-diphenyl-propyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.

PubMed: 19746975
DOI: 10.1021/jm9005302

実験手法

X-RAY DIFFRACTION (1.95 Å)