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

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 det...

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Published inJournal of medicinal chemistry Vol. 63; no. 8; pp. 4155 - 4170
Main Authors Kazmierski, Wieslaw M, Baskaran, Sam, Walker, Jill T, Miriyala, Nagaraju, Meesala, Ramu, Beesu, Mallesh, Adjabeng, George, Grimes, Richard M, Hamatake, Robert, Leivers, Martin R, Crosby, Renae, Xia, Bing, Remlinger, Katja
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 23.04.2020
Amer Chemical Soc
Subjects
Animals
Antiviral Agents - chemistry
Antiviral Agents - metabolism
Antiviral Agents - pharmacology
Chemistry, Medicinal
Dogs
Genotype
Humans
Life Sciences & Biomedicine
Mice
Pharmacology & Pharmacy
Rats
Rats, Wistar
Science & Technology
Viral Nonstructural Proteins - antagonists & inhibitors
Viral Nonstructural Proteins - metabolism
Virus Replication - drug effects
Virus Replication - physiology
DRUG
MEMBRANOUS REPLICATION
PHARMACOKINETICS
GSK2336805
RESISTANCE
ANTIVIRAL ACTIVITY
VIRUS NS5A
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b02176