Optimizing metabolic stability of phosphodiesterase 5 inhibitors: Discovery of a potent N-(pyridin-3-ylmethyl)quinoline derivative targeting synaptic plasticity.
Bioorg Med Chem Lett
; 92: 129409, 2023 08 15.
Article
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| MEDLINE
| ID: mdl-37453616
ABSTRACT
Phosphodiesterase 5 (PDE5) is a cyclic guanosine monophosphate-degrading enzyme involved in numerous biological pathways. Inhibitors of PDE5 are important therapeutics for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). We previously reported the first generation of quinoline-based PDE5 inhibitors for the treatment of AD. However, the short in vitro microsomal stability rendered them unsuitable drug candidates. Here we report a series of new quinoline-based PDE5 inhibitors. Among them, compound 4b, 8-cyclopropyl-3-(hydroxymethyl)-4-(((6-methoxypyridin-3-yl)methyl)amino)quinoline-6-carbonitrile, shows a PDE5 IC50 of 20 nM and improved in vitro microsomal stability (t1/2 = 44.6 min) as well as excellent efficacy in restoring long-term potentiation, a type of synaptic plasticity to underlie memory formation, in electrophysiology experiments with a mouse model of AD. These results provide an insight into the development of a new class of PDE5 inhibitors for the treatment of AD.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Quinolinas
/
Enfermedad de Alzheimer
Límite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos