Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold.
Bioorg Med Chem Lett
; 33: 127738, 2021 02 01.
Article
en En
| MEDLINE
| ID: mdl-33316404
ABSTRACT
Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1).
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Ácido Oxámico
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Compuestos Bicíclicos con Puentes
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Inhibidores Enzimáticos
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Indolamina-Pirrol 2,3,-Dioxigenasa
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Descubrimiento de Drogas
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Amidas
Límite:
Animals
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Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article