Discovery of novel inhibitors of phosphodiesterase 4 with 1-phenyl-3, 4-dihydroisoquinoline scaffold: Structure-based drug design and fragment identification. Issue 22 (15th November 2019)

• Record Type: Journal Article
• Authors: Liao, Yixian; Jia, Xiuhua; Tang, Yongmei; Li, Sumei; Zang, Yipeng; Wang, Lei; Cui, Zi-Ning; Song, Gaopeng
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 22(2019)
• Publication Date: 2019-11-15
• Subjects: Selective PDE4B inhibitors -- 1-Phenyl-3, 4-dihydroisoquinoline -- Synthesis -- Structure-activity relationships; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.126720
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: A series of 1-phenyl-3, 4-dihydroisoquinoline-3-carboxamide analogues6 –21 as selective PDE4B inhibitors were designed and synthesized based on structure-based drug design and fragment identification. Abstract: Currently, it is in urgent need to develop novel selective PDE4 inhibitors with novel structural scaffolds to overcome the adverse effects and improve the efficacy. Novel 1-phenyl-3, 4-dihydroisoquinoline amide derivatives were developed as potential PDE4 inhibitors based on the structure-based drug design and fragment identification strategy. A SARs analysis was performed in substituents attached in the C-3 side chain phenyl ring, indicating that the attachment of methoxy group or halogen atom substitution at the ortho -position of the phenyl ring was helpful to enhance both inhibitory activity toward PDE4B and selectivity. Compound15 with excellent selectivity, exhibited the most potent inhibition in vitro and in vivo, which is a promising lead for development of a new class of selective PDE4 inhibitors.