Open AccessDiscovery and Optimization of a 4-Aminopiperidine Scaffold for Inhibition of Hepatitis C Virus Assembly
Author(s) -
Adam Rolt,
Daniel C. Talley,
Seung Bum Park,
Zongyi Hu,
Andrés E. Dulcey,
Christopher Ma,
Parker Irvin,
Madeleine Leek,
Amy Q. Wang,
Andrew V. Stachulski,
Xin Xu,
Noel Southall,
Marc Ferrer,
T. Jake Liang,
Juan Marugán
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00696
Subject(s) - telaprevir , adme , virology , hepatitis c virus , drug discovery , chemistry , in vivo , potency , viral replication , in vitro , high throughput screening , virus , pharmacology , ribavirin , biology , biochemistry , microbiology and biotechnology
The majority of FDA-approved HCV therapeutics target the viral replicative machinery. An automated high-throughput phenotypic screen identified several small molecules as potent inhibitors of hepatitis C virus replication. Here, we disclose the discovery and optimization of a 4-aminopiperidine (4AP) scaffold targeting the assembly stages of the HCV life cycle. The original screening hit (1) demonstrates efficacy in the HCVcc assay but does not show potency prior to or during viral replication. Colocalization and infectivity studies indicate that the 4AP chemotype inhibits the assembly and release of infectious HCV. Compound 1 acts synergistically with FDA-approved direct-acting antiviral compounds Telaprevir and Daclatasvir, as well as broad spectrum antivirals Ribavirin and cyclosporin A. Following an SAR campaign, several derivatives of the 4AP series have been identified with increased potency against HCV, reduced in vitro toxicity, as well as improved in vitro and in vivo ADME properties.