Tetrahydroquinoline and tetrahydroisoquinoline derivatives as potential selective PDE4B inhibitors.
Bioorg Med Chem Lett
; 28(19): 3271-3275, 2018 10 15.
Article
em En
| MEDLINE
| ID: mdl-30131242
ABSTRACT
Tetrahydroquinoline and tetrahydroisoquinoline derivatives containing 2-phenyl-5-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds showed good inhibitory activity against PDE4B and blockade of LPS (lipopolysaccharide) induced TNF-α release, which also exhibited considerable in vivo activity in animal models of asthma/COPD (chronic obstructive pulmonary disease) and sepsis induced by LPS. The bioactivity of compounds containing tetrahydroquinoline (series 4) was higher than that of tetrahydroisoquinoline derivatives (series 3). Compound 4â¯m with 4-methoxybenzene moiety exhibited the best potential selective activity against PDE4B. The primary structure-activity relationship study and docking results showed that the tetrahydroquinoline moiety of compound 4â¯m played a key role to form hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Based on LPS induced sepsis model for the measurement of TNF-α inhibition in Swiss Albino mice and neutrophilia inhibition for asthma and COPD in Sprague Dawley rats with the potential molecules, compound 4â¯m would be great promise as a hit inhibitor in the future study.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Tetra-Hidroisoquinolinas
/
Inibidores da Fosfodiesterase 4
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article