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Discovery of Clinical Candidate (1R,4r)-44(R)-24(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
Journal article   Peer reviewed

Discovery of Clinical Candidate (1R,4r)-44(R)-24(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 Kumar, Jesse P. Waldo, Firoz A. Jaipuri, Agnieszka Marcinowicz, Clarissa Van Allen, James Adams, Tanay Kesharwani, Xiaoxia Zhang, Richard Metz, Angela J. Oh, …
Journal of medicinal chemistry, Vol.62(14), pp.6705-6733
07/25/2019
DOI: https://doi.org/10.1021/acs.jmedchem.9b00662
PMID: 31264862
Web of Science ID: WOS:000477785400018

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Abstract

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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