Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach.
ACS Med Chem Lett
; 11(12): 2510-2518, 2020 Dec 10.
Article
em En
| MEDLINE
| ID: mdl-33335675
ABSTRACT
Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
ACS Med Chem Lett
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos