Dihydrodibenzothiepine: Promising Hydrophobic Pharmacophore in the Influenza Cap-dependent Endonuclease Inhibitor.

Dihydrodibenzothiepine: Promising Hydrophobic Pharmacophore in the Influenza Cap-dependent Endonuclease Inhibitor.
Bioorg Med Chem Lett. 2020 Sep 11;:127547
Authors: Taoda Y, Miyagawa M, Akiyama T, Tomita K, Hasegawa Y, Yoshida R, Noshi T, Shishido T, Kawai M
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.
PMID: 32927030 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry Letters - September 10, 2020 Category: Chemistry Authors: Taoda Y, Miyagawa M, Akiyama T, Tomita K, Hasegawa Y, Yoshida R, Noshi T, Shishido T, Kawai M Tags: Bioorg Med Chem Lett Source Type: research