Design and synthesis of novel androgen receptor antagonists via molecular modeling.
Bioorg Med Chem
; 24(4): 789-801, 2016 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-26780832
ABSTRACT
Several androgen receptor (AR) antagonists are clinically prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds, 1e exhibited the strongest inhibitory effect on LNCaP cell growth (IC50=0.35µM) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biological results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied molecular modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chemical modifications.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Próstata
/
Desenho de Fármacos
/
Receptores Androgênicos
/
Antagonistas de Receptores de Andrógenos
/
Antineoplásicos
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2016
Tipo de documento:
Article