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

Euan A F Fordyce, Daniel W Brookes, Claire Lise-Ciana, Matthew S Coates, S Fraser Hunt, Kazuhiro Ito, John King-Underwood, Stuart T Onions, Guillaume F Parra, Garth Rapeport, Vladimir Sherbukhin, Jennifer A Stockwell, Peter Strong, Jennifer C Thomas, John Murray

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.

Ref: Bioorg Med Chem Lett 2017