Structure activity relationship studies of 3-arylsulfonyl-pyrido[1,2-a]pyrimidin-4-imines as potent 5-HT6 antagonists.
Bioorg Med Chem
; 22(5): 1782-90, 2014 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-24495863
ABSTRACT
Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2-4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure-activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores de Serotonina
/
Doença de Alzheimer
/
Iminas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article