Discovery of N-(2-benzyl-4-oxochroman-7-yl)-2-(5-(ethylsulfonyl) pyridin-2-yl) acetamide (b12) as a potent, selective, and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist.
Bioorg Chem
; 119: 105483, 2022 02.
Article
en En
| MEDLINE
| ID: mdl-34906860
ABSTRACT
The nuclear receptor retinoic acid receptor-related orphan receptor γ (RORγ, NR1F3, or RORc) exists in two isoforms, with one isoform (RORγ or RORc1) widely expressed in a variety of tissues, and the expression of the second isoform (RORγt or RORc2) restricted to the thymus and cells of the immune system. RORγt is a key regulator of the development and functions of T-helper 17 (Th17) cells. Clinical proof-of-concept (PoC) with small molecule inverse agonists of RORγt has been achieved with VTP-43742 (Phase II) for the treatment of psoriasis, and pre-clinical PoC for this mechanism has also been established for the treatment of autoimmune diseases. A series of aryl sulfonyl derivatives as novel RORγt inverse agonists were designed and synthesized based on VTP-43742. We conducted structural modifications that improved the activity profile. In pharmacodynamic (PD) studies, oral administration of compound b12 showed robust and dose-dependent inhibition of IL-6 and IL-17A cytokine expression. The ability of compound b12 to reduce the levels of IL-6 and IL-17A in vivo after oral dosing in mice, and a corresponding reduction in skin inflammation further supports the potential of small molecule RORγt modulation as a therapeutic target for the treatment of inflammatory diseases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Descubrimiento de Drogas
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Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Bioorg Chem
Año:
2022
Tipo del documento:
Article
País de afiliación:
China