Tetrahydroquinoline and tetrahydroisoquinoline derivatives as potential selective PDE4B inhibitors. Issue 19 (15th October 2018)

• Record Type: Journal Article
• Authors: Li, Ya-Sheng; Liu, Xing-Yu; Zhao, Dong-Sheng; Liao, Yi-Xian; Zhang, Lian-Hui; Zhang, Feng-Zhi; Song, Gao-Peng; Cui, Zi-Ning
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 19(2018)
• Page Start: 3271
• Page End: 3275
• Publication Date: 2018-10-15
• Subjects: Synthesis -- Tetrahydroquinoline -- Tetrahydroisoquinoline -- PDE4B inhibitor -- Molecular simulation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.04.068
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: 5-Phenyl-2-furan derivatives containing tetrahydro(iso)quinoline were synthesized. The title compounds as selective PDE4B inhibitors exhibited strong activity both in vitro and in vivo. SAR and molecular simulation studies were conducted. 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 (series4 ) was higher than that of tetrahydroisoquinoline derivatives (series3 ). Compound4 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 compound4 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, compound4 m would be great promise as a hit inhibitor in the future study.