Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile.
Eur J Med Chem
; 148: 477-486, 2018 Mar 25.
Article
em En
| MEDLINE
| ID: mdl-29477888
ABSTRACT
In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5.67â¯mL/min/kg) and moderate % plasma protein binding (53.71%). This was reflected onto increased in vivo exposure with a half-life greater than roflumilast by 3 folds (21â¯h) and a Cmax value of 113.958â¯ng/mL. Molecular docking attributed its good activity to its key binding interactions in PDE-4B active site with additional hydrogen bonding with amino acids lining the metal pocket. Summing up, 6c can be considered as suitable candidate for further investigation for the treatment of COPD.
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Base de dados:
MEDLINE
Assunto principal:
Benzamidas
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Doença Pulmonar Obstrutiva Crônica
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Inibidores da Fosfodiesterase 4
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Simulação de Acoplamento Molecular
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Aminopiridinas
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article