P4 cap modiﬁed tetrapeptidyl a-ketoamides
as potent HCV NS3 protease inhibitors
David X. Sun, Lifei Liu, Beverly Heinz, Alexander Kolykhalov, Jason Lamar,
Robert B. Johnson, Q. May Wang, Yvonne Yip and Shu-Hui Chen
Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 3 May 2004; accepted 26 May 2004
Available online 25 June 2004
Abstract—We describe herein the design, syntheses, and biological evaluation of new series of P4 tetrazole and adipic acid, ester,
amide capped tetrapeptidyl a-ketoamide based HCV protease inhibitors.
Ó 2004 Elsevier Ltd. All rights reserved.
Hepatitis C virus (HCV) infection has become a serious
health threat to our society, which poses risk of devel-
oping signiﬁcant morbidity and mortality.
hepatitis C is the leading cause for liver transplantation
in the USA. The Centers for Disease Control and Pre-
vention estimates that chronic HCV infection is
responsible for more than 10 thousands deaths annually.
The combination of pegylated-IFN-a and ribavirin is
now the standard therapy and produces a sustained
virologic response in about 80% of those infected with
genotypes 2 and 3 and 40% of patients infected with
genotype 1. Clearly, in order to provide better treatment
options for patients infected with genotype 1 virus, it is
imperative to develop antiviral therapeutic agents with
excellent eﬃcacy and acceptable side eﬀects proﬁles.
the various viral targets found with HCV, the NS3-4A
serine protease has been studied extensively.
covery of inhibitors for this enzyme has become the focus
of intense research for academic institutions and phar-
As documented in several recent
publications from Lilly
we embarked on
the design and systematic optimization (P1 through P4)
of tetrapeptidyl a-ketoamides as HCV protease inhibi-
tors. Parallel with these eﬀorts, we were also interested in
P4 cap modiﬁcation in hopes of improving enzyme
inhibitory potency as well as enzyme selectivity (e.g.
human neutrophil elastase). Toward this end, we de-
signed a new set of P2 hydroxyproline bearing inhibitors
3–5 with adipic acid, ester, or amide incorporated as their
respective P4 caps. It should be mentioned that these
initial designs were built upon the ﬁnding discovered by
our Vertex colleagues.
Consistent with the NS3 prote-
ase substrate preference at P5 and P6 sites (Asp and
Perni et al. reported that the P4 adipic acid
capped aldehyde 2 exhibited 2–4-fold improved enzyme
inhibitory potency relative to the P4 neutral (pyrazine)
capped inhibitor 1.
In addition, we decided to prepare
three P4 tetrazole
capped derivatives 6–8 as potential
HCV protease inhibitors because compound 6 was bio-
isostere of the P4 adipic acid capped inhibitor 3.
In view of the excellent enzyme inhibitory potency
exhibited by 6 (K
¼ 6 nM as listed in Table 1), we
decided later to expand the use of P4 tetrazole capping
strategy to P2 bicycloproline a-ketoamide inhibitor
series. Toward that end, in conjunction with P1
tions, we designed inhibitors 10, 12, and 15 for direct
scaﬀold comparison with their P2 TIQ-hydroxyproline
bearing counterparts 6–8 as shown in Figure 1. Fur-
thermore, with the intention to modulate cellular
activity or/and enzyme selectivity of the P2 bicyclopro-
line inhibitor series, we decided to incorporate addi-
tional neutral or polar P1
functionalities as seen in
compounds 11, 13, 14, and 16. On the other hand, to
take advantage of our recent P3 and P4 SAR ﬁnd-
we planed to prepare inhibitors 17–19 for
comparison with 9. In this manuscript, we report the
syntheses and antiviral activity evaluation of these P4
* Corresponding author. Tel.: +86-21-50462676; fax: +86-21-504610-
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0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
Bioorganic & Medicinal Chemistry Letters 14 (2004) 4333–4338