Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1.
Bioorg Med Chem Lett
; 88: 129280, 2023 05 15.
Article
em En
| MEDLINE
| ID: mdl-37054759
ABSTRACT
Starting from the dialkylaniline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor lead 3 (IDO1 HeLa IC50 = 7.0 nM), an iterative process of synthesis and screening led to cyclized analog 21 (IDO1 HeLa IC50 = 3.6 nM) which maintained the high potency of 3 while addressing issues of lipophilicity, cytochrome P450 (CYP) inhibition, hERG (human potassium ion channel Kv11.1) inhibition, Pregnane X Receptor (PXR) transactivation, and oxidative metabolic stability. An x-ray crystal structure of a biaryl alkyl ether 11 bound to IDO1 was obtained. Consistent with our earlier results, compound 11 was shown to bind to the apo form of the enzyme.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores Enzimáticos
/
Éteres
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article