Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1，2)-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.

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.