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Dihydrodibenzothiepine: Promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor.

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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Taoda Y,Miyagawa M,Akiyama T,Tomita K,Hasegawa Y,Yoshida R,Noshi T,Shishido T,Kawai M

doi

10.1016/j.bmcl.2020.127547

subject

Has Abstract

pub_date

2020-11-15 00:00:00

pages

127547

issue

22

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(20)30658-2

journal_volume

30

pub_type

杂志文章

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