Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 7, Number 13, 2007
Contents
New Approaches to the Treatment of Viral
Diseases
Guest Editor: Cristina Gardelli
Editorial Pp. 1249-1250
HIV Integrase Inhibitors: From Diketoacids to Hetero-cyclic
Templates: A History of HIV Integrase Medicinal Chemistry
at Merck West Point and Merck Rome (IRBM) Pp. 1251-1272
Melissa S. Egbertson
[Abstract]
An Update in the Development of HIV Entry Inhibitors
Pp. 1273-1289
Stefano Rusconi, Andrea Scozzafava, Antonio Mastrolorenzo
and Claudiu T. Supuran
[Abstract]
Macrocyclic Inhibitors of HCV NS3-4A Protease: Design
and Structure Activity Relationship Pp. 1290-1301
Srikanth Venkatraman and F. George Njoroge
[Abstract]
Recent Progress in the Development of Inhibitors of
the Hepatitis C Virus RNA-Dependent RNA Polymerase Pp.
1302-1329
Uwe Koch and Frank Narjes
[Abstract]
Molecule
of Month Pp. 1330
Abstracts
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Editorial
Epidemiological figures indicate that today 40 million people
are living with HIV/AIDS including 2.3 million children. 170
million people worldwide are infected with hepatitis C (HCV)
virus, with this being the second most common etiological
agent of chronic liver disease and hepatocellular carcinoma.
The four reviews in this issue discuss the most recent approaches
towards the care of these two types of viral diseases.
The first two contributions are dedicated to the most recent
strategies in the fight against AIDS. June 2006 marked the
25th anniversary of the discovery
of HIV/AIDS and since that fateful report on the 5h
June 1981, this disease has claimed the lives of over 25 million
people worldwide and it has afflicted every corner of the
world crossing geographic, cultural, ethnic and socioeconomic
boundaries. Currently, the therapy for AIDS relies on drugs
with three mechanisms: HIV protease, HIV reverse transcriptase
nucleoside and non nucleoside inhibitors. Unfortunately the
ability of the virus to mutate and become resistant to these
treatments has led to an increasing proportion of the infected
population harboring virus that is resistant to these classes
of drugs. In this issue the most promising scientific findings
about the discovery of two new classes of drugs will be presented:
Melissa S. Egbertson summarizes some of the developments in
Merck Laboratories on HIV Integrase Inhibitors and Claudiu
Supuran and coauthors illustrate the most recent progress
in the development of HIV entry inhibitors.
Melissa Egbertson describes efforts in the exploration of
Integrase activity and the design of potent and efficacious
inhibitors of HIV Integrase. An important step in the evolution
of the HIV Integrase program at Merck was the development
of a biochemical assay separating the final strand transfer
step from the earlier assembly and processing step; using
this assay, compounds were screened for their ability to act
solely as inhibitors of strand transfer. The evolution from
the diketoacid scaffold to the 1,6-naphthyridine template
is reported and the optimization route, towards compounds
selected for further preclinical evaluation, is described.
Claudiu T. Supuran and coauthors review the recent developments
in the field of HIV entry inhibitors. Viral entry into the
cell takes place in three steps: attachment of the virus to
the host cell through the formation of a complex between the
trimeric gp120–gp41 viral glycoproteins, the CD4 receptor
and the chemokine coreceptor (CCR5 or CXCR4); interaction
of the virus with the co-receptors and fusion of the virus
and host cell membranes. All three steps have been considered
for the design of HIV entry inhibitors and these different
types of agents have been reviewed by the authors. They also
underline the potential interference of these compounds with
homeostasis of the immune system and the possible risk of
inducing or shutting off inflammatory pathways. A careful
design to achieve selectivity over the host receptors is considered
of fundamental importance for the success of these agents.
The third and the fourth contributions are dedicated to the
efforts towards a therapy for Hepatitis C. Hepatitis C is
currently treated with PEGylated α-interferon
alone or in combination with ribavirin and no vaccine is available.
Up to 80% of genotype-2 infected patients respond to interferon
therapy whereas only about 50% of genotype-1 infected people
show a sustained response. In recent years drug development
efforts have mainly been directed at targeting inhibition
of two viral enzymes: NS3 protease and NS5B RNA dependent
RNA polymerase.
Srikanth Venkatraman and George Njoroge from Schering-Plough
summarize the efforts in their laboratories to identify HCV
protease inhibitors. They illustrate the strategy they employed
to depeptidize inhibitors of HCV NS3 protease. The shallow
active site along with the proximity of S1-S3 and S2-S4 sites
allowed them to explore macrocyclization as a possible tool
towards compounds with subnanomolar potencies and improved
pharmacological profiles, with better oral bioavailability
and longer half life than the corresponding acyclic precursors.
Frank Narjes and Uwe Koch from IRBM review the recent progress
in the development of inhibitors of the HCV NS5B RNA dependent
RNA Polymerase. This enzyme synthesizes RNA from the (+)-strand
RNA of the virus and has been shown to be essential for the
viral life-cycle. Since this activity is not present in mammalian
cells, and because success has been achieved with polymerase
inhibitors for HIV, NS5B RdRp has become a prime target for
drug discovery efforts. Several nucleoside inhibitors, which
bind to the active site of the enzyme, are now in advanced
clinical trials. In recent years a variety of novel small
molecule inhibitors of NS5B were discovered, which bind to
at least three distinct allosteric sites, but apart from one
example, they have only achieved proof-of-concept in the context
of the sub-genomic replicon assay. An update on active site
and allosteric inhibitors is provided, together with descriptions
of their binding mode and their ability to inhibit the main
genotypes of HCV.
I would like to thank Dr. Allen Reitz for having given me
the opportunity to write this issue. I’d like to thank
all the authors for their enthusiasm, time and dedication
in helping me to put this issue together and all the scientists
that very collaboratively have read and corrected the manuscripts.
The topics covered in this issue will certainly benefit many
of those who are engaged in the fight against these two viral
diseases and I hope will provide stimulating reading for other
medicinal chemists.
Cristina Gardelli
Senior Research Fellow
Department of Medicinal Chemistry
IRBM-MRL Rome
Via Pontina Km 30,600
00040 Pomezia, Roma
Italy
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HIV Integrase Inhibitors: From Diketoacids to Hetero-cyclic
Templates: A History of HIV Integrase Medicinal Chemistry
at Merck West Point and Merck Rome (IRBM)
Melissa S. Egbertson
Replication of the human immunodeficiency virus
(HIV) is dependent upon the enzyme HIV integrase (IN), one
of three essential enzymes encoded in the viral genome. HIV-1
IN catalyzes the insertion of the proviral DNA into the host
genome (strand transfer). HIV-1 IN therefore presents an attractive
chemotherapeutic target for the treatment of HIV infection
and AIDS that could provide patients and physicians with an
additional option for treatment. Assays were developed to
identify inhibitors of IN strand transfer. Diketoacid lead
compounds were explored and developed into a variety of heterocyclic
templates that are potent inhibitors of integrase strand transfer
with suitable medicinal chemical properties for treating HIV
infection and AIDS. The 1,6-naphthyridine L-870810 (Antiviral
activity in cells IC95 NHS
= 102 nM, n=237), was shown to be efficacious in reducing
viral RNA by 1.7 log units after doses of 400mg BID to HIV
infected patients. Optimization of physical properties led
to L-900564, an inhibitor of HIV IN that has excellent cell
potency in the presence of protein (Antiviral activity in
cells IC95 NHS = 16 nM, n=15),
excellent activity against mutants raised to HIV integrase
inhibitors, and a very good pharmacokinetic profile.
[Back to top]
An Update in the Development of HIV Entry
Inhibitors
Stefano Rusconi, Andrea Scozzafava, Antonio Mastrolorenzo
and Claudiu T. Supuran
HIV entry and fusion are two steps in the viral life cycle
that can be targeted by several classses of antiviral drugs.
The discovery of chemokines focused the attention on cellular
coreceptors used by the virus for entering within cells, and
to the various steps of such processes which are subject to
interactions with small molecules. Intense research led to
a wide range of effective compounds that are able to inhibit
these initial steps of viral replication. All steps in the
process of HIV entry into the cell may be targeted by specific
compounds that may be developed as novel types of antiretrovirals.
Thus, several inhibitors of the gp120 – CD4 interaction
have been detected so far (zintevir, FP-21399 and BMS-378806
in clinical trials). Small molecule chemokine receptor antagonists
acting as HIV entry inhibitors also were described in the
last period, which interact both with the CXCR4 coreceptor
(such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140),
or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220,
SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials),
together with new types of fusion inhibitors possessing the
same mechanism of action as enfuvirtide (such as T1249). Recently,
a third family of antivirals started to be used clinically
(in addition to the reverse transcriptase and protease inhibitors),
with the advent of enfuvirtide (T20), the first fusion inhibitor
to be approved as an anti-HIV agent. Some of these compounds
demonstrated in vitro synergism with other classes
of antivirals, offering thus the rationale for their combination
in therapies for HIV-infected individuals. Many HIV entry
and fusion inhibitors are currently investigated in controlled
clinical trials, and there are a number of them that is bioavailable
as oral formulations. This is an essential feature for an
extended use of these compounds with the purpose of ameliorating
adherence of patients to these medications and preventing
the development of drug resistance.
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Macrocyclic Inhibitors of HCV NS3-4A Protease:
Design and Structure Activity Relationship
Srikanth Venkatraman and F. George Njoroge
HCV NS3, a serine protease, that when bound to NS-4A cofactor
facilitates development of mature virons by catalyzing cleavage
of a single polyprotein to form functional and structural
proteins of HCV. X-ray structure of the enzyme reveal a very
shallow binding pocket at the catalytic site which makes development
of inhibitors a daunting task. Various novel approaches have
been used to design, preorganized, depeptidized macrocyclic
inhibitors linking the P1-P3
residues and P2-P4
groups. The design and structure activity relationship of
these macrocyclic inhibitors are reviewed in the following
article. X-ray structure of inhibitor bound to the active
site of the enzyme is also discussed. Macrocyclization proved
to be an effective tool for depeptidization of peptidic inhibitors,
imparting enhanced metabolic stability and improved pharmacokinetic
properties in the resultant molecules.
[Back to top]
Recent Progress in the Development of Inhibitors
of the Hepatitis C Virus RNA-Dependent RNA Polymerase
Uwe Koch and Frank Narjes
The global prevalence of hepatitis C virus (HCV) infection
and the serious consequences associated with the chronic state
of the disease have become a worldwide health problem. A combination
therapy comprising Interferon-alpha and Ribavirin represents
the current standard treatment for chronic HCV infection,
although it has demonstrated limited success and causes serious
side effects. Promising alternative approaches toward the
control of HCV infection include the development of small
molecule inhibitors of viral enzymes interfering with the
essential steps in the life cycle of the virus. In this review
we will focus on inhibitors of the HCV-encoded NS5B RNA-dependent
RNA polymerase (NS5B RdRp) which is essential for viral replication
and has been recognized as a prime target for therapeutic
intervention.
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