Highlights of the Structure–Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530)

Curative interferon
and ribavirin sparing treatments for hepatitis
C virus (HCV)-infected patients require a combination of mechanistically
orthogonal direct acting antivirals. A shared component of these treatments
is usually an HCV NS5A inhibitor. First generation FDA approved treatments,
including the component NS5A inhibitors, do not exhibit equivalent
efficacy against HCV virus genotypes 1–6. In particular, these
first generation NS5A inhibitors tend to select for viral drug resistance.
Ombitasvir is a first generation HCV NS5A inhibitor included as a
key component of Viekira Pak for the treatment of patients with HCV
genotype 1 infection. Since the launch of next generation HCV treatments,
functional cure for genotype 1–6 HCV infections has been achieved,
as well as shortened treatment duration across a wider spectrum of
genotypes. In this paper, we show how we have modified the anchor,
linker, and end-cap architecture of our NS5A inhibitor design template
to discover a next generation NS5A inhibitor pibrentasvir (ABT-530),
which exhibits potent inhibition of the replication of wild-type genotype
1–6 HCV replicons, as well as improved activity against replicon
variants demonstrating resistance against first generation NS5A inhibitors.