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Abstract Details
Discovery and Optimization of a 4-Aminopiperidine Scaffold for Inhibition of Hepatitis C Virus Assembly
J Med Chem. 2021 Jul 8;64(13):9431-9443. doi: 10.1021/acs.jmedchem.1c00696.Epub 2021 Jun 29.
Adam Rolt1, Daniel C Talley2, Seung Bum Park1, Zongyi Hu1, Andrés Dulcey2, Christopher Ma1, Parker Irvin1, Madeleine Leek1, Amy Q Wang2, Andrew V Stachulski3, Xin Xu2, Noel Southall2, Marc Ferrer2, T Jake Liang1, Juan J Marugan2
Author information
1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, United States.
2Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
3The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K.
Abstract
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.