6R7D

Crystal structure of LTC4S in complex with AZ13690257

Summary for 6R7D

• Entry DOI: 10.2210/pdb6r7d/pdb
• Descriptor: Leukotriene C4 synthase, (1~{S},2~{S})-2-[5-[cyclopropylmethyl(naphthalen-1-yl)amino]-4-methoxy-pyrimidin-2-yl]carbonylcyclopropane-1-carboxylic acid, NICKEL (II) ION, ... (6 entities in total)
• Functional Keywords: inhibitor, arachidonic acid cascade, cysteinyl leukotrienes, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 12
• Total formula weight: 226807.33

Authors

Kack, H.,Ek, M. (deposition date: 2019-03-28, release date: 2019-08-28, Last modification date: 2024-01-24)

Primary citation

Munck Af Rosenschold, M.,Johannesson, P.,Nikitidis, A.,Tyrchan, C.,Chang, H.F.,Ronn, R.,Chapman, D.,Ullah, V.,Nikitidis, G.,Glader, P.,Kack, H.,Bonn, B.,Wagberg, F.,Bjorkstrand, E.,Andersson, U.,Swedin, L.,Rohman, M.,Andreasson, T.,Bergstrom, E.L.,Jiang, F.,Zhou, X.H.,Lundqvist, A.J.,Malmberg, A.,Ek, M.,Gordon, E.,Pettersen, A.,Ripa, L.,Davis, A.M.
Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1S,2S)-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.
J.Med.Chem., 62:7769-7787, 2019

PubMed Abstract: 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.

PubMed: 31415176
DOI: 10.1021/acs.jmedchem.9b00555

Experimental method

X-RAY DIFFRACTION (2.35 Å)