Discovery of novel PDE10 inhibitors by a robust homogeneous screening assay.
Acta Pharmacol Sin
; 34(8): 1116-20, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23603978
ABSTRACT
AIM:
To develop a homogeneous assay for high-throughput screening (HTS) of inhibitors of phosphodiesterase 10 (PDE10).METHODS:
Purified human PDE10 enzyme derived from E coli, [(3)H]-cAMP and yttrium silicate microbeads were used to develop an HTS assay based on the scintillation proximity assay (SPA) technology. This method was applied to a large-scale screening campaign against a diverse compound library and subsequent confirmation studies. Preliminary structure-activity relationship (SAR) studies were initiated through limited structural modifications of the hits.RESULTS:
The IC50 value of the control compound (papaverine) assessed with the SPA approach was comparable and consistent with that reported in the literature. Signal to background (S/B) ratio and Z' factor of the assay system were evaluated to be 5.24 and 0.71, respectively. In an HTS campaign of 71 360 synthetic and natural compounds, 67 hits displayed reproducible PDE10 inhibition, of which, 8 were chosen as the scaffold for structural modifications and subsequent SAR analysis.CONCLUSION:
The homogeneous PDE10 SPA assay is an efficient and robust tool to screen potential PDE10 inhibitors. Preliminary SAR studies suggest that potent PDE10 inhibitors could be identified and developed through this strategy.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Papaverina
/
Inibidores de Fosfodiesterase
/
Diester Fosfórico Hidrolases
/
Descoberta de Drogas
/
Ensaios de Triagem em Larga Escala
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article