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The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex

  • Nicholas A. MeanwellEmail author
  • Makonen Belema
Chapter
Part of the Topics in Medicinal Chemistry book series

Abstract

The discovery of the hepatitis C virus (HCV) NS5A replication inhibitor daclatasvir (1) had its origins in a phenotypic screening lead. However, during the optimization campaign, it was observed that some members of the chemotype underwent a radical dimerization under the assay conditions. This redirected the effort to focus on palindromic molecules, a species subsequently shown to complement the dimeric nature of the NS5A protein. The most challenging aspect of the discovery program was extending antiviral activity to encompass GT-1a virus which was accomplished only after the development of extensive structure-activity relationships. In clinical trials, oral administration of daclatasvir (1) produced a profound effect on viral load with onset that was more rapid than had been seen previously with either NS3 protease or NS5B polymerase inhibitors. A groundbreaking clinical trial that combined daclatasvir (1) with the protease inhibitor asunaprevir (52) established that a chronic HCV infection could be cured with small molecule therapy in the absence of immune stimulation, setting the stage for approval of this regimen for the treatment of GT-1b-infected subjects by the Japanese health authorities on July 4, 2014.

Keywords

Asunaprevir Beclabuvir Daclatasvir Dimerization Hepatitis C virus NS5A inhibitor, NS3 protease inhibitor Sofosbuvir Synergy 

Notes

Compliance with Ethical Standards

Conflict of Interest The authors are employees of Bristol-Myers Squibb and own company stock.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Discovery ChemistryBristol-Myers Squibb Research and DevelopmentPrincetonUSA
  2. 2.Department of Discovery Chemistry and Molecular TechnologiesBristol-Myers Squibb Research and DevelopmentPrincetonUSA

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