Download MendeleyDiscovery 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.
Kumar, S., Waldo, J.P., Jaipuri, F.A., Marcinowicz, A., Van Allen, C., Adams, J., Kesharwani, T., Zhang, X., Metz, R., Oh, A.J., Harris, S.F., Mautino, M.R.(2019) J Med Chem 62: 6705-6733
- PubMed: 31264862
- DOI: https://doi.org/10.1021/acs.jmedchem.9b00662
- Primary Citation of Related Structures:
6O3I - PubMed Abstract:
A 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.
Organizational Affiliation:
NewLink Genetics Corporation , Ames , Iowa 50010 , United States.
