Bioorganic & Medicinal Chemistry Letters
Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 1:
C2-Symmetric inhibitors with diyne and biphenyl linkers
Simon Giroux a, , Darius Bilimoria , Caroline Cadilhac , Kevin M. Cottrell , Francois Denis ,
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Evelyne Dietrich , Nigel Ewing , James A. Henderson , Lucille L’Heureux , Nagraj Mani ,
Mark Morris , Olivier Nicolas , T. Jagadeeswar Reddy , Subajini Selliah , Rebecca S. Shawgo ,
Jinwang Xu , Nathalie Chauret , Francoise Berlioz-Seux , Laval C. Chan , Sanjoy K. Das
Anne-Laure Grillot , Youssef L. Bennani , John P. Maxwell
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Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA 02210, USA
Vertex Pharmaceuticals Canada Inc., 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada
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a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery of C -symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two
2
Received 24 October 2014
Revised 10 December 2014
Accepted 12 December 2014
Available online 30 December 2014
straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This
study revealed the paramount importance of the aromatic character of the linker to achieve high geno-
type 1a potency.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
NS5a
HCV
Hepatitis C
Thienoimidazole
The hepatitis C virus currently affects an estimated 130–
70 million people worldwide.1 Long-term HCV infection leads to
NS5A is essential for RNA replication5 and virion assembly6
but its exact role is still unclear. Thus, the elucidation of
NS5A’s role remains an active area of investigation.7 Several
NS5A inhibitors are currently under clinical investigations with
1
many different diseases such as liver fibrosis, liver cirrhosis and
1
hepatocellular carcinoma (HCC). Since 2011, the standard of care
8
9
(
SOC) has evolved from a two-drug combination (pegylated
daclatasvir (Bristol-Myers Squibb), ledipasvir (Gilead Sciences),
1
0
11
12
interferon-
interferon-
a
a
+ ribavirin) to a three-drug combination (pegylated
+ ribavirin + NS3Á4A inhibitor). The addition of an
ABT-267
(AbbVie), MK-8742
(Merck) and GSK-2336805
(GlaxoSmithKline) being the frontrunners. Very recently, the
Ò
NS3Á4A protease inhibitor, such as Incivek™ or Victrelis™, greatly
increases the sustained virological response (SVR) and reduces
the treatment duration.2 Despite this significant progress, the
resistance profiles and genotypic coverages of the current SOC reg-
imens could still be dramatically improved. Moreover, a regimen
FDA granted approval for Gilead’s Harvoni , the first once-daily
single tablet regimen for the treatment of patients with
chronic genotype 1 infections. HarvoniÒ consists of a combi-
nation of sofosbuvir (NS5B inhibitor) and ledipasvir (NS5A
inhibitor).
13
that would abolish injections of pegylated interferon-
desirable and is a current focus in ongoing clinical trials.
a
is highly
One requisite feature of several NS5A inhibitors, originating
from the ground-breaking work of Bristol-Myers-Squibb,8 is the
presence of imidazole moieties flanking phenyl or aromatic linkers
that join terminal methylcarbamate-capped pyrrolidine-valine
groups. In several cases, the imidazole rings can be fused to a
phenyl ring such as in ledipasvir (Gilead) in which the resulting
benzimidazole is highlighted in red (Fig. 1). A [5,5]-bicyclic
moiety such as a thienoimidazole appeared to us as a logical
choice in our search of novel chemical entities in the NS5A area.
Herein, we describe our early synthetic efforts leading to potent
thienoimidazole-based HCV NS5A inhibitors.
3
Currently, the most investigated inhibitor classes are the NS3Á4A
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b
1b
protease inhibitors, the NS5B polymerase inhibitors and the
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b,4
NS5A inhibitors.
Unlike the NS3Á4A protease and the NS5B polymerase, NS5A
has no known enzymatic function. It has been shown that
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Corresponding author.
Present address: AngioChem, 201 President-Kennedy Ave., Suite PK-2880,
Montreal, QC H2X 3Y7, Canada.
0
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.