Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel RORγt inverse agonists.
Bioorg Med Chem Lett
; 30(17): 127392, 2020 09 01.
Article
en En
| MEDLINE
| ID: mdl-32738966
ABSTRACT
A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirrolidinas
/
Diseño de Fármacos
/
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2020
Tipo del documento:
Article