2054-00-4Relevant academic research and scientific papers
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.
Experimental and computational analysis of supramolecular motifs involving Csp2(aromatic)-F and CF3 groups in organic solids
Panini, Piyush,Gonnade, Rajesh G.,Chopra, Deepak
, p. 4981 - 5001 (2016/07/06)
A detailed experimental (SCXRD) and theoretical (PIXEL and QTAIM) investigation of the evolution of different supramolecular motifs formed via the presence of both C(sp2)/(sp3)-F groups in the crystal packing has been performed in a
