title: Discovery of a potent respiratory syncytial virus RNA polymerase inhibitor.
abstract: Targeting viral polymerases has been a proven and attractive strategy for antiviral drug discovery. Herein we describe our effort in improving the antiviral activity and physical properties of a series of benzothienoazepine compounds as respiratory syncytial virus (RSV) RNA polymerase inhibitors. The antiviral activity and spectrum of this class was significantly improved by exploring the amino substitution of the pyridine ring, resulting in the discovery of the most potent RSV A polymerase inhibitors reported to date.
authors.affiliation: Infection Innovative Medicine, AstraZeneca Pharmaceuticals, 35 Gatehouse Lane, Waltham, MA 02451, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Melinda
authors.initials: M
authors.lastname: Foulk
authors.forename: Lisa
authors.initials: L
authors.lastname: Aschenbrenner
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.forename: Choi-Lai
authors.initials: CL
authors.lastname: Tiong-Yip
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Johnson
authors.forename: Demetri
authors.initials: D
authors.lastname: Moustakas
authors.forename: Paul R
authors.initials: PR
authors.lastname: Fleming
authors.forename: Dean G
authors.initials: DG
authors.lastname: Brown
authors.forename: Minli
authors.initials: M
authors.lastname: Zhang
authors.forename: Douglas
authors.initials: D
authors.lastname: Ferguson
authors.forename: Dedong
authors.initials: D
authors.lastname: Wu
authors.forename: Qin
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D012136:Respiratory Syncytial Viruses / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001381:Azepines; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D012321:DNA-Directed RNA Polymerases
keywords: Antiviral; Polymerase inhibitor; Respiratory syncytial virus