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.
J Med Chem
; 62(14): 6705-6733, 2019 07 25.
Article
em En
| MEDLINE
| ID: mdl-31264862
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores Enzimáticos
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Indolamina-Pirrol 2,3,-Dioxigenase
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Imidazóis
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Indóis
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article