Discovery of novel benzothienoazepine derivatives as potent inhibitors of respiratory syncytial virus

Bioorg Med Chem Lett. 2017 May 15;27(10):2201-2206. doi: 10.1016/j.bmcl.2017.03.053. Epub 2017 Mar 23.

Abstract

The development of novel non-nucleoside inhibitors of the RSV polymerase complex is of significant clinical interest. Compounds derived from the benzothienoazepine core, such as AZ-27, are potent inhibitors of RSV viruses of the A-subgroup, but are only moderately active against the B serotype and as yet have not demonstrated activity in vivo. Herein we report the discovery of several novel families of C-2 arylated benzothienoazepine derivatives that are highly potent RSV polymerase inhibitors and reveal an exemplary structure, compound 4a, which shows low nanomolar activity against both RSV A and B viral subtypes. Furthermore, this compound is effective at suppressing viral replication, when administered intranasally, in a rodent model of RSV infection. These results suggest that compounds belonging to this chemotypes have the potential to provide superior anti-RSV agents than those currently available for clinical use.

Keywords: Antiviral; Polymerase inhibitor; RSV.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • Azepines / chemical synthesis
  • Azepines / chemistry*
  • Azepines / pharmacology
  • Azepines / therapeutic use
  • DNA-Directed RNA Polymerases / antagonists & inhibitors
  • DNA-Directed RNA Polymerases / metabolism
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Humans
  • Mice
  • Respiratory Syncytial Virus Infections / drug therapy
  • Respiratory Syncytial Viruses / drug effects
  • Respiratory Syncytial Viruses / enzymology
  • Serogroup
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Azepines
  • DNA-Directed RNA Polymerases