Structure-Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines.
J Med Chem
; 58(18): 7572-9, 2015 Sep 24.
Article
em En
| MEDLINE
| ID: mdl-26322748
ABSTRACT
Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Antimaláricos
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
África do Sul