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Discovery of Clinical Candidate (1R,4r)-4-((R)-2-((S)-6-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1.

Sanjeev KumarJesse P WaldoFiroz A JaipuriAgnieszka MarcinowiczClarissa Van AllenJames AdamsTanay KesharwaniXiaoxia ZhangRichard MetzAngela J OhSeth F HarrisMario R Mautino
Published in: Journal of medicinal chemistry (2019)
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.
Keyphrases
  • structure activity relationship
  • small molecule
  • positron emission tomography
  • molecular docking
  • high throughput
  • computed tomography
  • anti inflammatory
  • emergency department
  • adverse drug
  • electronic health record