Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile

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-alpha concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro aim (5.67 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 (21 h) and a C-max value of 113.958 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. (C) 2018 Elsevier Masson SAS. All rights reserved.