Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of Keap1-Nrf2 protein-protein interaction.
Bioorg Med Chem
; 28(6): 115343, 2020 03 15.
Article
em En
| MEDLINE
| ID: mdl-32046917
ABSTRACT
The Keap1-Nrf2-ARE system represents a crucial antioxidant defense mechanism that protects cells against reactive oxygen species. Targeting Keap1-Nrf2 protein-protein interaction (PPI) has become a promising drug target for several oxidative stress-related and inflammatory diseases including pulmonary fibrosis, chronic obstructive pulmonary disorder (COPD) and cancer chemoprevention. For the development of a potential therapeutic agent, drug-like properties and potency are important considerations. In this work, we focused on the modification of 4 as a lead through a molecular dissection strategy in an effort to improve its metabolic stability, leading to the discovery of a series of new disubstituted xylylene derivatives. The preliminary SAR of 9a indicated that compound 21a containing S-methylated acetate moieties exhibited comparable potency to the lead compound 4 in a fluorescent polarization assay but with improved metabolic stability in the presence of human liver microsomes.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator 2 Relacionado a NF-E2
/
Bibliotecas de Moléculas Pequenas
/
Descoberta de Drogas
/
Proteína 1 Associada a ECH Semelhante a Kelch
/
Naftalenos
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article