Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 14, Pages 6705-6733Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00662
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Funding
- NewLink Genetics Corporation
- Genentech, Inc.
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A novel class of 5-substituted 5H-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 5H-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.
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