6R7D

Crystal structure of LTC4S in complex with AZ13690257

6R7D の概要

• エントリーDOI: 10.2210/pdb6r7d/pdb
• 分子名称: Leukotriene C4 synthase, (1~{S},2~{S})-2-[5-[cyclopropylmethyl(naphthalen-1-yl)amino]-4-methoxy-pyrimidin-2-yl]carbonylcyclopropane-1-carboxylic acid, NICKEL (II) ION, ... (6 entities in total)
• 機能のキーワード: inhibitor, arachidonic acid cascade, cysteinyl leukotrienes, membrane protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 226807.33

構造登録者

Kack, H.,Ek, M. (登録日: 2019-03-28, 公開日: 2019-08-28, 最終更新日: 2024-01-24)

主引用文献

Munck Af Rosenschold, M.,Johannesson, P.,Nikitidis, A.,Tyrchan, C.,Chang, H.F.,Ronn, R.,Chapman, D.,Ullah, V.,Nikitidis, G.,Glader, P.,Kack, H.,Bonn, B.,Wagberg, F.,Bjorkstrand, E.,Andersson, U.,Swedin, L.,Rohman, M.,Andreasson, T.,Bergstrom, E.L.,Jiang, F.,Zhou, X.H.,Lundqvist, A.J.,Malmberg, A.,Ek, M.,Gordon, E.,Pettersen, A.,Ripa, L.,Davis, A.M.
Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic Acid (AZD9898) as a New Treatment for Asthma.
J.Med.Chem., 62:7769-7787, 2019

PubMed Abstract: While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl leukotriene cascade. Starting from a screening hit (), a program to discover oral inhibitors of LTC4S led to (1,2)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (), a picomolar LTC4S inhibitor (IC = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC = 34 nM). Compound mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound with a human dose predicted to be 30 mg once daily.

PubMed: 31415176
DOI: 10.1021/acs.jmedchem.9b00555

実験手法

X-RAY DIFFRACTION (2.35 Å)