GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage

  • J Med Chem. 2020 Apr 23;63(8):4155-4170. doi: 10.1021/acs.jmedchem.9b02176.
Wieslaw M Kazmierski  1 ,  Sam Baskaran  1 ,  Jill T Walker  1 ,  Nagaraju Miriyala  1 ,  Ramu Meesala  1 ,  Mallesh Beesu  1 ,  George Adjabeng  1 ,  Richard M Grimes  1 ,  Robert Hamatake  1 ,  Martin R Leivers  1 ,  Renae Crosby  1 ,  Bing Xia  2 ,  Katja Remlinger  1
Affiliations
  • 1. GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.
  • 2. GlaxoSmithKline, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
PMID: 32202782 DOI: 10.1021/acs.jmedchem.9b02176
Abstract

Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV Inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.

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