Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists.
Bioorg Med Chem Lett
; 29(16): 2265-2269, 2019 08 15.
Article
en En
| MEDLINE
| ID: mdl-31257087
ABSTRACT
An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Pirrolidinas
/
Sulfonas
/
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2019
Tipo del documento:
Article