6r7d

Crystal structure of LTC4S in complex with AZ13690257

spinqualitylabelsall models 6r7d, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6r7d is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.35Å Ligands: JUQ, LMT, NI, PLM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 PubMed While 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Leukotriene C4 synthase

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