Design, synthesis and structure-activity relationship of novel tricyclic benzimidazolone derivatives as potent 18 kDa translocator protein (TSPO) ligands.
Bioorg Med Chem
; 21(5): 1257-67, 2013 Mar 01.
Article
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| MEDLINE
| ID: mdl-23352481
ABSTRACT
The 18 kDa translocator protein (TSPO) was identified as a discrete receptor for diazepam (1). Since TSPO in the central nervous system (CNS) is believed to regulate neurosteroids biosynthesis, selective TSPO ligands are expected to be useful in the treatment of psychiatric disorders. We synthesized three novel tricyclic benzimidazolone derivatives, and selected the dihydroimidazoquinolinone derivative 27 as a lead TSPO ligand. Study of the structure-activity relationship (SAR) of dihydroimidazoquinolinone derivatives revealed compounds with potent affinity for TSPO (subnanomolar K(i) values), but poor metabolic stability. The optimization of these compounds led to compound 48 with potent affinity for TSPO and good in vitro PK profile.
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Banco de datos:
MEDLINE
Asunto principal:
Bencimidazoles
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Diseño de Fármacos
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Proteínas Portadoras
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Receptores de GABA-A
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Compuestos Heterocíclicos con 3 Anillos
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Acetanilidas
Límite:
Animals
Idioma:
En
Año:
2013
Tipo del documento:
Article