Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 5, Number 16, 2005
Contents
Protease Inhibitors in Drug Discovery
Guest Editor: Francis X. Tavares
Editorial Pp.1587
Discovery of Next Generation Inhibitors
of HIV Protease Pp.1589
Andrew Spaltenstein, Wieslaw M. Kazmierski, John F. Miller
and Vicente Samano
[Abstract]
Recent Developments of Structure Based β-Secretase
Inhibitors for Alzheimer’s Disease Pp.1609
Arun K Ghosh, Nagaswamy Kumaragurubaran and Jordan Tang
[Abstract]
Inhibitors of Dipeptidyl Peptidase IV – Recent
Advances and Structural Views Pp.1623
Daniel Hunziker, Michael Hennig and Jens-Uwe Peters
[Abstract]
Design of Cathepsin K Inhibitors for Osteoporosis
Pp.1639
David N. Deaton and Francis X. Tavares
[Abstract]
Small Molecule Coagulation Cascade Inhibitors in the
Clinic Pp.1677
Eddine Saiah and Chris Soares
[Abstract]
Caspase Inhibitors: A Pharmaceutical Industry
Perspective Pp.1697
Steven D. Linton
[Abstract]
Abstracts
[Back to top]
Editorial
Protease Inhibitors in Drug Discovery
Proteases are important for maintenance of physiological functions
in the body. A dysregulation of their activity can sometimes
be detrimental to the normal physiological functions resulting
in diseases specific to the activity of the proteolytic enzyme
involved. Structure-based design has been the hallmark of
protease inhibitor design work leading to identification of
potent and selective inhibitors within as well as between
various classes of proteases. Although most of the early work
in the design of protease inhibitors involved peptidomimetic
scaffolds, there is an increasing emphasis to develop nonpeptidic
inhibitors that may provide better pharmacokinetic profiles.
This issue, devoted to protease inhibitors, highlights the
advancements in extremely important therapeutic areas.
The emergence of HIV protease inhibitors has dramatically
altered the course of the mortality associated with HIV infection.
The emergence of new resistant viral strains combined with
noncompliance associated with side effects and heavy dosing
schedules, present a formidable challenge in the treatment
of this disease. The authors describe the development of the
next generation of HIV protease inhibitors that surpasses
the limitations of current antiviral treatments and has shown
promise in the clinic.
Alzheimer’s disease, a neurodegenerative disorder has
attracted tremendous attention with the discovery of aspartyl
proteases such as β-and γ-secretases
that are involved in the cleavage of Aβ precursor protein
to amyloid β peptides that form plaques, a pathological
feature of Alzheimer’s disease. Based on pioneering
work described herein, by Ghosh et al. in identifying peptidic
scaffolds for β-secretase, a number of companies have
patented inhibitors that are modifications of these scaffolds.
It is hoped that these drugs will address mortality issues
that are not met with standard acetyl cholinesterase inhibitors
that address only the cognitive functions.
Diabetes is a multifactorial disease associated with increase
in cardiovascular disease, renal dysfunction, and nephropathy.
The association of the most commonly used antidiabetics such
as PPAR modulators with weight gain and edema has necessitated
the development of approaches that would offer beneficial
advantages. Potentiation of endogenous GLP-1 by inhibiting
its degradation using DPPIV inhibitors has gained momentum
as the next generation of antidiabetics. The authors have
provided an overview of structural classes of DPPIV inhibitors
along with discussion of binding modes. Promising clinical
data from several companies has also been discussed.
The development of cathepsin K inhibitors for the treatment
of osteoporosis has received considerable attention. The high
expression of this enzyme in osteoclasts along with genetic
studies highlights the importance of this enzyme in osteoporosis.
The authors describe the evolution of simple aldehyde based
inhibitors to potent, selective and orally bioavailable ketoamide-based
inhibitors with in vivo efficacy. There are several companies
with compounds in the clinic that demonstrate in vivo efficacy
in postmenopausal women.
Deep vein thrombosis and pulmonary embolism are major causes
of morbidity and mortality. Although heparin and warfarin
are drugs commonly used for treatment, these have significant
downsides. The review on coagulation cascade focuses on inhibitors
of factor Xa, a key enzyme common to both the intrinsic as
well as extrinsic pathways. In addition, the review also covers
direct thrombin inhibitors. The review focuses mainly on clinical
aspects of the drugs that have potential for treatment of
these ailments.
Caspases are aspartyl proteases that are involved in apoptosis.
Imbalance of the apoptotic pathway results in the pathogenesis
of diseases including inflammation and cancer. The review
on caspases focuses on recent advances in the field with emphasis
on drugs in the clinic. Since these enzymes regulate cell
survival and are also ubiquitous, outcomes of these clinical
trials are eagerly awaited.
I would like to thank all the authors for their enthusiasm,
time and dedication in helping to put this issue together.
The topics covered in this issue will certainly benefit many
of those who are engaged in areas specific to proteases and
I hope would provide stimulating reading for the general reader
Dr. Francis X. Tavares
Department of Medicinal Chemistry
GlaxoSmithkline Research Laboratories
Research Triangle Park, NC,
USA
[Back to top]
Discovery of Next Generation Inhibitors of HIV Protease
Andrew Spaltenstein, Wieslaw M. Kazmierski, John F. Miller
and Vicente Samano
Due to factors such as resistance and long-term side effects
as well as dosing regimen-related adherence issues, HIV therapy
is a constantly moving target. HIV-1 protease inhibitors had
an immediate and dramatic impact on the outcome of HIV/AIDS
when launched in late 1995, and the search for new and improved
next generation molecules has been under way in many laboratories.
At GlaxoSmithKline (GSK) and Vertex Pharmaceuticals, this
effort focused on two key issues, patient compliance and viral
resistance. Using a water-solubilizing prodrug approach, the
pill-burden in delivering our protease inhibitor, amprenavir,
was dramatically decreased. By eliminating the large amounts
of excipients necessary for the original soft-gel formulation,
fosamprenavir (Lexiv a®/Telzir®)
delivers the clinically efficacious dose of amprenavir with
two compact tablets per dose, compared to eight gel capsules.
Our efforts to overcome viral resistance to 1st generation
protease inhibitors by further elaborating the SAR of the
amprenavir and related scaffolds, led to successive and dramatic
improvements in wild-type antiviral potencies, and ultimately
to the discovery of “ultra-potent” molecules with
very favorable overall resistance profiles. The selection
of GW640385 (brecanvir – USAN approved only) as a clinical
candidate and its progression into current phase 2 dose ranging
studies represents the culmination of our effort toward next
generation protease inhibitors.
[Back to top]
Recent Developments of Structure Based β-Secretase
Inhibitors for Alzheimer’s Disease
Arun K Ghosh, Nagaswamy Kumaragurubaran and Jordan Tang
The amyloid-β (Aβ) peptide is the principal components
of the senile plaques found in the brains of patients with
Alzheimer’s disease (AD). The poorly soluble 40-42 amino
acid peptide, formed from the cleavage of the Aβ precursor
protein (APP) by two proteases, is believed to play a central
role in the pathogenesis of AD. β-Secretase (memapsin
2, BACE1), a membrane-anchored aspartic protease, is responsible
for the initial step of APP cleavage leading to the generation
of Aβ. Identification and structural determination of
β-secretase have established it to be a primary drug
target for AD therapy and stimulated active studies on the
inhibitors of this protease. Here we review more recent developments
in the design and testing of structure-based β-secretase
inhibitors.
[Back to top]
Inhibitors of Dipeptidyl Peptidase IV – Recent
Advances and Structural Views
Daniel Hunziker, Michael Hennig and Jens-Uwe Peters
Prevalence of type 2 diabetes has increased dramatically
in the last decades. Current medicines are not yet capable
to efficiently prevent or reverse progression of the disease
and its associated comorbidities. As a consequence, there
is a great need for novel antidiabetic drugs. Treatments of
type 2 diabetes that are based on enhanced and sustained action
of insulinotropic incretin hormones such as GLP-1 have received
much attention in the past years. Treatment strategies include
administration of: 1) GLP-1 analogues that are resistant to
degradation by the serine protease DPP-IV, and 2) small molecule
DPP-IV inhibitors that are able to provide sustained action
of endogenous GLP-1, again by preventing its degradation.
This review summarizes recent research results for the second
approach. It briefly touches upon the advantages that treatment
of type 2 diabetes with DPP-IV inhibitors may offer over current
medications. In the main section, several important structural
classes of DPP-IV inhibitors are described and compared based
on literature data. Specific attention is given to the analysis
of several X-ray structures of enzyme-inhibitor co-crystals.
Finally, as clinical data are steadily emerging for some of
the most advanced development candidates, the last section
of this review is providing a brief overview of some efficacy
data from recent clinical studies with DPP-IV inhibitors.
[Back to top]
Design of Cathepsin K Inhibitors for Osteoporosis
David N. Deaton and Francis X. Tavares
Osteoporosis is a progressive, debilitating bone disease
resulting in increased cost and morbidity to the elderly.
This review summarizes the therapeutic approaches taken in
the treatment of osteoporosis with particular emphasis on
cathepsin K inhibitors. Cathepsin K, a cysteine protease predominantly
expressed in osteoclasts, is a key player involved in bone
matrix degradation. Both genetic ablation and small molecule
inhibitor strategies versus cathepsin K have validated the
importance of this enzyme in bone resorption. Starting from
aldehyde-based leads, this review synopsizes the design of
improved small molecule inhibitors by GlaxoWellcome researchers.
These efforts involved the evaluation of various warheads,
including cyanamides, ketoheterocycles, and ketoamides. Initial
structure/activity relationships of aldehyde-based inhibitors
proved useful in the design of ketoamide-based cathepsin K
inhibitors. Further exploration of S3, S2,
S1, and S1’ subsites with P3,
P2, P1, and P1’ probes
have resulted in the identification of potent, selective,
orally bioavailable ketoamide-based inhibitors of cathepsin
K with demonstrated in vivo efficacy.
[Back to top]
Small Molecule Coagulation Cascade Inhibitors in the
Clinic
Eddine Saiah and Chris Soares
Venous thromboembolic disease, including deep vein thrombosis
and pulmonary embolism, is a cause of significant mortality
and morbidity. For several decades, anticoagulant options
for the treatment and prevention of thrombosis have been limited
mainly to agents such as unfractionated heparin and oral vitamin
K antagonists such as warfarin. Although these therapies have
proven benefits, they also have important limitations that
result in their underuse in routine clinical practice. A variety
of novel anticoagulants with improved pharmacologic and clinical
profiles are in development, offering benefits over traditional
therapies. Specifically, progress has been made in the development
of small molecule Factor Xa inhibitors and thrombin inhibitors.
The most advanced drugs reviewed include DPC-423, DPC-602,
razaxaban, GSK’s 813893, Portola’s Xa inhibitors
(formerly Millennium), otamixaban, DU-176b, KFA-1982, BAY-59-7939,
DX-9065a, YM-150, LY-517717, Exanta, 3DP’s thrombin
inhibitors, SSR-182289, LB-30057, LB-30870, BIBR-1048 and
Merck’s thrombin inhibitors. With their potentially
consistent and predictable pharmacological profile, oral formulation,
and decreased need for coagulation monitoring, these new agents
will likely increase the use and duration of anticoagulation
treatment in thromboembolic disorders and reduce the burden
associated with long-term management.
[Back to top]
Caspase Inhibitors: A Pharmaceutical Industry Perspective
Steven D. Linton
Caspase inhibition has been demonstrated to be therapeutically
effective in moderating excessive programmed cell death, or
apoptosis. Publications detailing programs in the pharmaceutical
industry have been more frequent in recent years, ranging
from SAR studies to clinically relevant animal models of disease.
A summary of the work published in this exciting new area
is presented, outlining the broad applicability of this fundamental
cellular mechanism across several disease indications. This
area of research has matured to the level of advancing compounds
into clinical trials: VX-74 (Pralnacasan) and VX-765 as anti-inflammatory
agents, and IDN-6556, a pan-caspase inhibitor as an anti-apoptotic
agent.
|
