AZD9898
目录号 : GC64919AZD9898 是一种口服有效的白三烯-C4 合成酶 (LTC4S) 抑制剂,IC50 值为 0.28 nM。AZD9898 减轻GABA 结合和肝毒性信号。AZD9898 可用于哮喘的研究。
Cas No.:2042347-69-1
Sample solution is provided at 25 µL, 10mM.
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AZD9898 is an orally active leukotriene-C4 synthetase (LTC4S, glutathione S-transferase II) inhibitor, with an IC50 of 0.28 nM. AZD9898 mitigates the GABA binding and hepatic toxicity signal. AZD9898 has the potential to treat asthma[1].
AZD9898 with the single dose of 100 mg/kg is well tolerated and no safety concerns are raised[1].
[1]. Munck Af RosenschÖld M, et al. 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. 2019 Aug 30.
Cas No. | 2042347-69-1 | SDF | Download SDF |
分子式 | C20H19ClF3N3O4 | 分子量 | 457.83 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.1842 mL | 10.9211 mL | 21.8422 mL |
5 mM | 0.4368 mL | 2.1842 mL | 4.3684 mL |
10 mM | 0.2184 mL | 1.0921 mL | 2.1842 mL |
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Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1 S,2 S)-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 2019 Sep 12;62(17):7769-7787.PMID:31415176DOI:10.1021/acs.jmedchem.9b00555
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 (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.