Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors.
Bioorg Med Chem
; 25(20): 5709-5717, 2017 10 15.
Article
em En
| MEDLINE
| ID: mdl-28888661
Improvement of subtype selectivity of an inhibitor's binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D. Among these derivatives, compound 12 showed both the strongest inhibition activity (IC50=0.60µM) as well as good selectivity against PDE4B and good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary SAR study showed that restricting the conformation of the catechol moiety in rolipram with the scaffold of oxazolidinone-fused tetrahydroisoquinoline could lead to an increase in selectivity for PDE4B over PDE4D, which was consistent with the observed docking simulation.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Tetra-Hidroisoquinolinas
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article