2946-73-8Relevant articles and documents
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
Munck Af Rosensch?ld, Magnus,Johannesson, Petra,Nikitidis, Antonios,Tyrchan, Christian,Chang, Hui-Fang,R?nn, Robert,Chapman, Dave,Ullah, Victoria,Nikitidis, Grigorios,Glader, Pernilla,K?ck, Helena,Bonn, Britta,W?gberg, Fredrik,Bj?rkstrand, Eva,Andersson, Ulf,Swedin, Linda,Rohman, Mattias,Andreasson, Theresa,Bergstr?m, Eva Lamm,Jiang, Fanyi,Zhou, Xiao-Hong,Lundqvist, Anders J.,Malmberg, Anna,Ek, Margareta,Gordon, Euan,Pettersen, Anna,Ripa, Lena,Davis, Andrew M.
supporting information, p. 7769 - 7787 (2019/10/11)
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.
Acetanilide and bromoacetyl-lysine derivatives as activators for human histone deacetylase 8
Mukhtar, Yusif M.,Huang, Yajun,Liu, Jiajia,Chen, Di,Zheng, Weiping
supporting information, p. 2319 - 2323 (2017/05/09)
In the current study, seven compounds (i.e. 1–7) were found to be novel activators for the Nε-acetyl-lysine deacetylation reaction catalyzed by human histone deacetylase 8 (HDAC8). When assessed with the commercially available HDAC8 peptide substrate Fluor-de-Lys-HDAC8 that harbors the unnatural 7-amino-4-methylcoumarin (AMC) residue immediately C-terminal to the Nε-acetyl-lysine residue to be deacetylated, our compounds exhibited comparable activation potency to that of TM-2-51, the strongest HDAC8 activator reported in the current literature. However, when assessed with an AMC-less peptide substrate derived from the native HDAC8 non-histone substrate protein Zinc finger protein ZNF318, while our compounds were all found to be able to activate HDAC8 deacetylation reaction, TM-2-51 was found not to be able to. Our compounds also seemed to be largely selective for HDAC8 over other classical HDACs. Moreover, treatment with the strongest activator among our compounds (i.e. 7) was found to decrease the KM of the above AMC-less HDAC8 substrate, while nearly maintaining the kcat of the HDAC8-catalyzed deacetylation on this substrate.
A new, convenient and selective 4-dimethylaminopyridine-catalyzed trifluoroacetylation of anilines with ethyl trifluoroacetate
Prashad,Hu,Har,Repic,Blacklock
, p. 9957 - 9961 (2007/10/03)
A new, convenient, and selective 4-dimethylaminopyridine-catalyzed trifluoroacetylation of anilines with ethyl trifluoroacetate is described. Anilines, containing other functional groups, e.g. alcohols, phenols, hindered secondary amines, and secondary anilines, are also selectively trifluoroacetylated in high yields under these newly developed conditions. (C) 2000 Elsevier Science Ltd.
