Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms

  • J Med Chem. 2017 Jan 12;60(1):290-306. doi: 10.1021/acs.jmedchem.6b01310.
Ling Tong ,  Wensheng Yu ,  Lei Chen ,  Oleg Selyutin ,  Michael P Dwyer ,  Anilkumar G Nair ,  Robert Mazzola ,  Jae-Hun Kim ,  Deyou Sha ,  Jingjun Yin ,  Rebecca T Ruck ,  Ian W Davies ,  Bin Hu  1 ,  Bin Zhong  1 ,  Jinglai Hao  1 ,  Tao Ji  1 ,  Shuai Zan  1 ,  Rong Liu ,  Sony Agrawal ,  Ellen Xia ,  Stephanie Curry ,  Patricia McMonagle ,  Karin Bystol ,  Frederick Lahser ,  Donna Carr ,  Laura Rokosz ,  Paul Ingravallo ,  Shiying Chen ,  Kung-I Feng ,  Mark Cartwright ,  Ernest Asante-Appiah ,  Joseph A Kozlowski
Affiliations
  • 1. Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China.
PMID: 27808515 DOI: 10.1021/acs.jmedchem.6b01310
Abstract

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV Infection.

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