6o3i
From Proteopedia
Crystal Structure of Human IDO1 bound to navoximod (NLG-919)
Structural highlights
FunctionI23O1_HUMAN Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1] Publication Abstract from PubMedA novel class of 5-substituted 5 H-imidazo[5,1- a]isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5 H-imidazo[5,1- a]isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure-activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties. Discovery of Clinical Candidate (1 R,4 r)-4-(( R)-2-(( S)-6-Fluoro-5 H-imidazo[5,1- a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1.,Kumar S, Waldo JP, Jaipuri FA, Marcinowicz A, Van Allen C, Adams J, Kesharwani T, Zhang X, Metz R, Oh AJ, Harris SF, Mautino MR J Med Chem. 2019 Jul 2. doi: 10.1021/acs.jmedchem.9b00662. PMID:31264862[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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