Journal of Medicinal Chemistry p. 7769 - 7787 (2019)
Update date:2022-08-15
Topics:
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.
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.
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