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

European Journal of Medicinal Chemistry
Bahia A MoussaMarwa A Fouad

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(5.67 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 Cmaxvalue 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.

Citations

Nov 12, 2020·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jennifer M K NguyenVenkataramana K Sidhaye
Jan 8, 2021·European Journal of Medicinal Chemistry·Nathalia Fonseca NadurArthur Eugen Kümmerle

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