6r7d | pdb_00006r7d
Crystal structure of LTC4S in complex with AZD9898
Structural highlights
Disease[LTC4S_HUMAN] Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:246530]. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly. Function[LTC4S_HUMAN] Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4. Publication Abstract from PubMedWhile bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show the cysteine leukotriene cascade remains highly activated in some asthmatics, even those on high dose inhaled or oral corticosteroids. Hence inhibition of LTC4S enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteine leukotriene cascade. Starting from a screening hit 3, a program to discover oral inhibitors of LTC4S led to AZD9898 (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (PBMC 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 30 mg q.d. Discovery of the Oral Leukotriene-C4 Synthetase Inhibitor (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-met hoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) as a New Treatment for Asthma.,Munck Af Rosenschold M, Johannesson P, Nikitidis A, Tyrchan C, Chang HF, Ronn R, Chapman D, Ullah V, Nikitidis G, Glader P, Kack H, Bonn BK, Wagberg F, Bjorkstrand E, Andersson U, Swedin L, Rohman M, Andreasson T, Lamm Bergstr Ouml M E, Jiang F, Zhou X, Lundqvist A, Malmberg A, Ek ME, Gordon E, Pettersen A, Ripa L, Davis AM J Med Chem. 2019 Aug 15. doi: 10.1021/acs.jmedchem.9b00555. PMID:31415176[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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