Dihydrodibenzothiepine: Promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor. Issue 22 (15th November 2020)

• Record Type: Journal Article
• Authors: Taoda, Yoshiyuki; Miyagawa, Masayoshi; Akiyama, Toshiyuki; Tomita, Kenji; Hasegawa, Yasushi; Yoshida, Ryu; Noshi, Takeshi; Shishido, Takao; Kawai, Makoto
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 22(2020)
• Publication Date: 2020-11-15
• Subjects: Influenza -- Cap-dependent endonuclease -- Carbamoyl pyridone -- Chelator -- Hydrophobic pharmacophore -- Dihydrodibenzothiepine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127547
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitor with a carbamoyl pyridone bicycle (CAB) scaffold. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indices, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine is the most promising pharmacophore. The compound ( S )-13i showed potent virus titer reduction over oseltamivir phosphate in an in vivo mouse model. The CAB compound described herein served as the lead compound of baloxavir marboxil with a tricyclic scaffold, which was approved in Japan and the USA in 2018.