Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 7, Number 4, 2007
Contents
Receptor Dimerization and Bivalent Ligands,
an Emerging Topic for Drug Design
Guest Editor: Dr. Ao Zhang
Editorial Pp. 341
Receptor Dimerization - Rationale for
the Design of Bivalent Ligands Pp. 343-345
Ao Zhang, Zhili Liu and Ying Kan
[Abstract]
Agonist and Antagonist Bivalent Ligands for Serotonin
and Dopamine Receptors Including Their Transporters
Pp. 347-353
Michael Decker and Jochen Lehmann
[Abstract]
Probing the Membrane Targeting C1 Subdomains
of PKC with Bivalent Ligands Pp. 355-362
Ireneusz Nowak
[Abstract]
Kappa Receptor Bivalent Ligands Pp.
363-373
Xuemei Peng and John L. Neumeyer
[Abstract]
Bivalent Ligands Derived from Huperzine a as
Acetylcholinesterase Inhibitors Pp. 375-387
H. Haviv, D.M. Wong, I. Silman and J.L. Sussman
[Abstract]
Viagra’s Cousins - Towards a New Generation
of Phosphodiesterase Inhibitors
Guest Editor: Philip Thompson
Editorial Pp. 389
Crystal Structures of Phosphodiesterases and Implications
on Substrate Specificity and Inhibitor Selectivity
Pp. 391-403
Hengming Ke and Huanchen Wang
[Abstract]
Design of Second Generation Phosphodiesterase 5 Inhibitors
Pp. 405-419
Michael J. Palmer, Andrew S. Bell, David N. A. Fox and
David G. Brown
[Abstract]
Re-Discovering PDE3 Inhibitors - New Opportunities
for a Long Neglected Target Pp. 421-436
Philip E. Thompson, Vincent Manganiello and Eva Degerman
[Abstract]
The Novel Functions of cGMP-Specific Phosphodiesterase
5 and its Inhibitors in Carcinoma Cells and Pulmonary/ Cardiovascular
Vessels Pp. 437-454
Bing Zhu and Samuel J. Strada
[Abstract]
Corrigendum Pp. 455
Abstracts
[Back to top]
Editorial
The rapid advances of molecular biology, neuropharmacology,
anatomy, gene cloning, and recombinant DNA techniques have
unravelled our understanding of a large number of receptors.
An increasing number of secondary and tertiary structures
of these receptors are being disclosed. Further, an increasing
number of receptors have been reported recently to dimerize
or oligomerize, which opens a new vistas to receptor researchers.
The biology, pharmacology, function and utility of such phenomenon,
as well as how receptor dimerization/ oligomerization can
guide drug design and discovery are being extensively investigated.
In this issue of Current Topics in Medicinal Chemistry,
we highlight several aspects of the receptor dimerization
and bivalent ligands of the most developed receptors by collecting
comprehensive reviews from several experts working in this
emerging field.
In the first article, Zhang and Kan discussed the most recent
advances in the receptor dimerization phenomenon. Several
key elements regarding this process are postulated and discussed.
The utility of this common feature of receptors to guide drug
design and development are confirmed, and the critical considerations
leading to the successful discovery of bivalent drugs are
presented.
Decker and Lehmann reviewed bivalent ligands developed for
dopamine and serotonin receptors, as well as their respective
transporters reported within the last two decades. They pointed
out that increased potency, selectivity and CNS penetration
for 5-HT1B/1D
receptor agonists could be achieved with the bivalent ligands.
Bivalent dopamine receptor agonists and antagonists can exhibit
selectivity profiles very different from their monomeric analogues
without loss in potency.
Nowak presented the progress of bivalent ligands for probing
the membrane targeting C1 subdomains of protein kinase C (PKC),
a family of ubiquitously expressed signal transducing proteins.
Novel and conventional subfamilies of PKC have two C1 domains,
C1A and C1B. Bivalent PKC ligands are designed to activate
simultaneously both C1 domains. Many bivalent ligands displayed
1-2 orders of magnitude higher potency than their monovalent
congeners with the “dimeric” ligands containing
10-14 carbon spacers being the most effective.
Peng and Neumeyer presented a comprehensive review of the
most developed kappa(κ)
opioid receptor bivalent ligands. κ
Agonists and antagonist ligands such as norBNI and BNI have
been used as tools to elucidate the κ
receptor characteristics. Bivalent ligands may also be effective
analgesics although none have this far been used clinically.
Structure-activity relationships and molecular modeling has
led to the development of a more potent and selective κ
antagonist (GNTI). In addition, novel hetero-bivalent ligands
with high mixed κ/μ
or mixed κ/δ
affinity and intriguing pharmacological properties are also
discussed. It is pointed out that such bivalent ligands have
great potential as novel analgesics with fewer adverse side
effects, and as alternative treatment for drug abuse.
Haviv, Wong, Silman and Sussman commented on the bivalent
ligands derived from Huperzine A as an acetylcholine-sterase
(AchE) inhibitors. The naturally occurring alkaloid Huperzine
A (HupA) has been used for centuries as a Chinese folk medicine
from its source plant Huperzia Serrata. Its pharmacological
profile has now led to its use as a promising drug for the
treatment of Alzheimer's disease. Biochemical and crystallographic
studies of AChE revealed two potential binding sites in the
active-site of AChE, initiating the development of Huperzine
A-based bivalent ligands. Extensive studies have been conducted
by these authors as well as by others, and are summarized
in this manuscript. The advantages and disadvantages of such
a bivalent ligand approach are also presented.
Ao Zhang, Ph.D.
Shanghai Institute of Materia Medica
Chinese Academy of Sciences,
555 Zuchongzhi Lu, Pudong
Shanghai, China 201203
John L. Neumeyer, Ph.D.
Medicinal Chemistry Laboratory
Harvard Medical School, McLean Hospital
115 Mill Street, Belmont, MA, 02478,
USA
[Back to top]
Receptor Dimerization - Rationale for the Design of
Bivalent Ligands
Ao Zhang, Zhili Liu and Ying Kan
Accumulating evidence has confirmed the existence and
functional significance of GPCR and other types of receptor
homodimers and heterodimers. However, many aspects of the
biology and pharmacology of the dimerization process remain
unclear. Several crystal structures of the dimerized proteins
or protein-ligand complex have provided useful insights to
the understanding of such process. As a common phenomenon
of most receptors, homodimerization and heterodimerization
have added a new dimension to characterize the receptor different
from the traditional way, and open a new avenue to rational
drug design and discovery.
[Back to top]
Agonist and Antagonist Bivalent Ligands for Serotonin
and Dopamine Receptors Including Their Transporters
Michael Decker and Jochen Lehmann
This review deals with the literature (1982-2006) concerning
bivalent ligands for dopamine (D) and serotonin (5-HT) receptors,
as well as for their respective transporters. The design,
synthesis, and pharmacological evaluation of bivalent agonists
and antagonists for dopamine and serotonin receptors have
been successfully pursued. Increased potencies for 5-HT1B/1D
receptor agonists were achieved as well as improved selectivities.
At these receptors, selectivity seems to depend strongly on
spacer length, whereas the improved affinities seem to be
based on the presence of two pharmacophores within one molecule.
Intrinsic activities and pharmacokinetic properties may differ
from those of the respective monovalent ligands. Additionally,
improved central nervous system penetration was achieved.
Bivalent dopamine receptor agonists and antagonists can exhibit
selectivity profiles different from their monomeric analogues
with no loss in potency. For dopamine antagonists, affinities
depend strongly on spacer length. For agonistic dimers different
pharmacokinetic properties were observed. Bivalency was also
applied to inhibitors of monoamine re-uptake transporters.
Selectivity profiles and affinities depend strongly on the
length of the alkylene-spacer: For some dimeric inhibitors
the norepinephrine transporter (NET) and the dopamine transporter
(DAT) affinities changed gradually, but for the serotonin
transporter (SERT) a pentamethylene spacer showed the highest
potency. Because the bivalent ligand approach has just begun
to be applied to these versatile, therapeutically important
targets, many advances in affinity enhancement, as well as
the achievement of novel selectivity profiles and improved
pharmacokinetics can be expected.
[Back to top]
Probing the Membrane Targeting C1 Subdomains
of PKC with Bivalent Ligands
Ireneusz Nowak
Protein kinase C is a family of ubiquitously expressed
signal transducing proteins. The hallmark for PKC activation
is its translocation to membranes following generation of
lipid second messengers. This process is mediated by C1 and
C2 membrane-targeting modules, whose engagement on membranes
provides energy for a conformational change crucial to PKC
activity. Novel and conventional subfamilies of PKC have two
C1 domains, namely C1A and C1B, each of which contain a binding
pocket for a messenger. Several studies addressed the issue
of simultaneous activation of both C1 domains by specifically
designed bivalent activators based on phorbol esters, benzolactam
and other PKC ligands. Many bivalent ligands displayed 1-2
orders of magnitude higher potency then their monovalent congeners.
Most effective were the “dimeric” ligands linked
with 10-14 carbon spacers. Lower than predicted potency and
lack of marked isoform selectivity indicate that those compounds
do not activate both C1 domains at the same time, or that
process is unfavored due to steric or conformational reasons.
However, high binding affinity for some of them provides hope
that related PKC activators that are isoform selective can
be developed. As to the nature of the linkers: flexible and
lipophilic oligomethylene chains proved superior over flexible
and hydrophilic oligoethylene glycol or rigid and lipophilic
benzene in recruiting PKC to the membranes.
[Back to top]
Kappa Receptor Bivalent Ligands
Xuemei Peng and John L. Neumeyer
Bivalent ligands of κ
opioid agonists and antagonists, such as norBNI and BNI, are
used as tools to elucidate the κ
receptor characteristics. Bivalent ligands may also be effective
analgesics although none have this far been used clinically.
Structure-activity relationships (SAR) and molecular modeling
led to the development of a more potent and selective kappa
antagonist (5’-guanidinylnaltrindole, GNTI). Novel homo
and hetero bivalent ligands with high mixed κ/μ
or mixed κ/δ
affinity and intriguing pharmacological properties may eventually
lead to useful analgesics with fewer adverse side effects.
Bivalent ligands were also developed that could act as probes
of the receptor-oligomerzation and organization phenomena.
A structurally unique κ
antagonist (JDTic) provides an additional tool to characterize
κ opioid
receptor.
[Back to top]
Bivalent Ligands Derived from Huperzine a as
Acetylcholinesterase Inhibitors
H. Haviv, D.M. Wong, I. Silman and J.L. Sussman
The naturally occurring alkaloid Huperzine A (HupA) is
an acetylcholinesterase (AChE) inhibitor that has been used
for centuries as a Chinese folk medicine in the context of
its source plant Huperzia Serrata. The potency and
relative safety of HupA rendered it a promising drug for the
ameliorative treatment of Alzheimer's disease (AD) vis-à-vis
the "cholinergic hypothesis" that attributes the
cognitive decrements associated with AD to acetylcholine deficiency
in the brain. However, recent evidence supports a neuroprotective
role for HupA, suggesting that it could act as more than a
mere palliative. Biochemical and crystallographic studies
of AChE revealed two potential binding sites in the active-site
gorge of AChE, one of which, the “peripheral anionic
site” at the mouth of the gorge, was implicated in promoting
aggregation of the beta amyloid (Aβ)
peptide responsible for the neurodegenerative process in AD.
This feature of AChE facilitated the development of dual-site
binding HupA-based bivalent ligands, in hopes of concomitantly
increasing AChE inhibition potency by utilizing the "chelate
effect", and protecting neurons from Aβ
toxicity. Crystal structures of AChE allowed detailed modeling
and docking studies that were instrumental in enhancing the
understanding of underlying principles of bivalent inhibitor-enzyme
dynamics. This monograph reviews two categories of HupA-based
bivalent ligands, in which HupA and HupA fragments serve as
building blocks, with a focus on the recently solved crystallographic
structures of Torpedo californica AChE in complex
with such bifunctional agents. The advantages and drawbacks
of such structured-based drug design, as well as species differences,
are highlighted and discussed.
[Back to top]
Editorial
In this issue of Current Topics in Medicinal Chemistry, four
review articles have been compiled to exemplify the state-of-the-art
in the design and application of phosphodiesterase inhibitors.
This is not a new topic; for fifty years chemists have been
called upon to provide novel compounds that inhibit this family
of enzymes and it has been these compounds, in league with
advances in cellular and molecular biology that have helped
unravel the complexities of the cyclic nucleotide second messenger
systems.
In the last decade however, one advance has thrust this research
area back to the forefront of contemporary drug design –
the successful clinical application of sildenafil (Viagra)
as a medication for male erectile dysfunction (MED). The commercial
and clinical success of Viagra, a PDE5 inhibitor and its PDE5
inhibiting competitors, vardenafil and tadalafil, essentially
won the argument that PDE inhibitors could be successful modern
drugs, and thus provided the evidential weight to push PDE-based
research proposals into fruition in industry and academia
alike. Of course, PDE5 is but one isoform of this enzyme family,
which continues to grow with gene splicing variants emerging
across the various pharmacologically and genomically defined
family of 11 members including over 60 sub-types. Significant
drug discovery efforts have resulted in a number of current
clinical candidates against PDE4-related diseases, and significant
research efforts against other isoforms.
Overall though, the capacity to identify PDE isoforms currently
outstrips our ability to characterise their roles in physiology
or pathology, and the state of knowledge regarding many of
the PDE isoforms is superficial or controversial. This brings
us to something of a Catch 22 in respect of advance in the
PDE field. Typically, medicinal chemistry campaigns are not
undertaken without some observation of a therapeutic potential
relating to a selected biological target. However, in the
case of the majority of PDEs, such therapeutic potential still
is some distance short of validation. This is mainly due to
the lack of pharmacological inhibitors. It is thus down to
the groups with the curiosity and opportunity to look, not
just for drugs but for the crucial reagents which will fuel
discovery biology in what is a fundamental component of the
circuitry of the cell.
In deference to the most significant recent technological
breakthroughs, the articles show the powerful application
of x-ray crystallography as a tool for drug discovery. Hengming
Ke, who was the first to describe the crystal structure of
the catalytic domain PDE4, together with Huanchen Wang surveys
the burgeoning crystal data released since 2000, to explore
what that information tell us about the origins of substrate
specificity and inhibitor selectivity across PDE classes.
Another contribution comes from the laboratories where Viagra
was developed at Pfizer in Sandwich, UK. Michael Palmer, Andrew
Bell, David Fox and David Brown show the power of high throughput
crystallography and screening, in accelerating the hit to
lead process for discovery of second generation PDE5 inhibitors.
A pharmacological perspective on PDE5 beyond MED is provided
by Bing Zhu and Samuel Strada, from University of Sth. Alabama,
who have examined the role of that enzyme together with other
cGMP-hydrolyzing isoforms in diseases such as cancer with
the clinical candidate, Exisulind and its analogues. They
also explore the return of PDE5 inhibition to its “first
home” in the study of pulmonary hypertension, and describe
the discoveries that are validating PDE5 inhibition as a target
in this therapeutic area.
Finally, Eva Degerman, Vince Manganiello and I have turned
our attention to the need for new PDE3 inhibitors as pharmacological
tools and potential therapeutics. An area largely neglected,
since the 1990’s on the back of clinical failures, the
advances in molecular biology, structural biology and cell
physiology demand revived activity in the area. We attempt
to distill the mass of medicinal chemistry from the 1980’s
and 1990’s to discover new opportunities in the field,
particularly with respect to PDE3 sub-types, PDE3A and PDE3B.
Necessarily, these articles are limited to reviewing a small
subset of the range of isoforms of current and future interest.
Inhibitors of those less famous isoforms such as PDE2, PDE7
and PDE9 are emerging regularly in the patent and peer-reviewed
literature and it seems likely that there maybe a real prospect
of having available isoform-selective inhibitors at PDEs 1
- 11, and many that can distinguish between sub-types. Hopefully
however, there is something to be retrieved in each review
for researchers in the field of PDE inhibition that might
inspire a worthwhile experiment.
I thank Dr. Allen Reitz for the invitation to prepare this
collection; it is humbling to present the offerings of a number
of major players in the field of PDE research and I thank
them for their willingness to participate and embrace the
themes of this issue. Their conceptual and technical approaches
are certainly those that will advance research in the PDE
field.
Philip Thompson
Department of Medicinal Chemistry
Victorian College of Pharmacy
Monash University
Parkville 3052
Australia
[Back to top]
Crystal Structures of Phosphodiesterases and Implications
on Substrate Specificity and Inhibitor Selectivity
Hengming Ke and Huanchen Wang
Crystal structures of seven phosphodiesterase families (PDE1-5,
7, 9) show a conserved core catalytic domain that contains
about 300 amino acids and fourteen α-helices.
The catalytic domains of the PDE families 1-4, 7, and 9 have
a uniform conformation. However, the H-loop at the active
site of PDE5 shows four different conformations upon binding
of inhibitors, probably implying a special mechanism for recognition
of substrates and inhibitors by PDE5. The active site of all
PDE families contains two divalent metal ions: zinc and probably
magnesium. The PDE4-AMP and PDE5-GMP structures reveal the
conserved interactions of the phosphate groups of the products
AMP and GMP, and thus suggest a universal mechanism of nucleophilic
attack for all PDE families. The substrate specificity has
not been well understood. This review will comment on the
early proposal, “glutamine switch”, on basis of
the recent biochemical and structural information. The PDE-inhibitor
structures have identified a common subpocket for non-selective
binding of all inhibitors and potential elements for recognition
of family-selective inhibitors. The kinetic analysis on the
mutations of PDE7 to PDE4 suggests that the multiple elements
must work together to define inhibitor selectivity.
[Back to top]
Design of Second Generation Phosphodiesterase 5 Inhibitors
Michael J. Palmer, Andrew S. Bell, David N. A. Fox and
David G. Brown
The clinical significance of phosphodiesterase 5 (PDE5) inhibition
is increasingly understood following the pioneering work with
sildenafil, and the continuing development programmes for
both sildenafil and other marketed inhibitors. Since the initial
launch of sildenafil for male erectile dysfunction (MED),
approval has now been granted for treatment of pulmonary hypertension,
whilst ongoing studies have indicated the potential of PDE5
inhibition for the treatment of a range of additional indications
including cardioprotection, memory retention and diabetes.
Many of these additional indications are best suited to chronic
oral dosing and emphasise the need for highly selective inhibitors
with extended duration of action. This article will focus
on a research programme aimed at the discovery of improved
second-generation PDE5 inhibitors. Essential features of these
new PDE5 inhibitors would be enhanced selectivity across the
whole PDE family and pharmacokinetics compatible with once
daily dosing. Key elements used in this programme are high
throughput screening (HTS), exploitation of co-crystal structural
information for bound inhibitor in the PDE5 active site, and
employment of parallel chemistry to speed progress. Under
the guidance of co-crystal structural information, a non-selective
HTS hit with poor physicochemistry was initially modified
using parallel chemistry to give a lead compound (3)
that established a new PDE5 inhibitor series. Notably, (3)
displayed physicochemistry compatible with a long plasma half-life,
and wide chemical scope. Subsequent optimisation of (3)
using crystal structure information to guide design, led rapidly
to highly potent and selective PDE5 inhibitors (47,
50). Continued focus on physical properties through
ligand efficiency evaluation and lipophilicity (cLogP), maintained
the inherently desirable physicochemistry of the initial lead.
[Back to top]
Re-Discovering PDE3 Inhibitors - New Opportunities
for a Long Neglected Target
Philip E. Thompson, Vincent Manganiello and Eva Degerman
The PDE3 enzymes or “low Km cGMP-inhibited phosphodiesterases”
have long been established as important mediators of cellular
physiology, and synthetic PDE3 inhibitors have been critical
to the delineation of the enzymes’ roles. Yet despite
decades of progress on the biology of these enzymes, the medicinal
chemistry landscape relating to PDE3 inhibitors has remained
essentially unchanged since the mid 1990’s. Up until
then the field was at the cutting edge of drug design; without
the tools of molecular and structural biology, molecules of
high potency were being achieved using logical pharmacophore
models and lead modification. Yet virtually all the impetus
went out of this area on the back of failures at the clinic
and PDE3 as a therapeutic target largely fell out of favour.
A decade later and with the “new” technologies
of structural and molecular biology breathing new life into
PDE3 research in general, PDE3 inhibitors are sought for target
validation in an array of therapeutic applications.
In this review, we examine the current state of PDE3 research;
firstly we summarize the structural and functional properties
of PDE3 enzymes with particular attention to the heterogeneity
within this class of enzymes which differ markedly in expression,
localisation and means of regulation across various tissue
types. It is the structural and functional complexity of the
PDE3 enzymes that underpins the re-emergence of PDE3s roles
as targets for drug design. We then look at past clinical
evaluation of PDE3 inhibitors that occurred without that information
and which may have had a significant bearing on the outcome
of those drug discovery efforts. Finally we look at current
approaches to the design of PDE3 inhibitors which utilize
that historic data but also incorporate new inputs from structural
biology and combinatorial chemistry.
[Back to top]
The Novel Functions of cGMP-Specific Phosphodiesterase
5 and its Inhibitors in Carcinoma Cells and Pulmonary/ Cardiovascular
Vessels
Bing Zhu and Samuel J. Strada
PDE5 is a key enzyme involved in the regulation of cGMP-specific
signaling pathways in normal physiological processes such
as smooth muscle contraction and relaxation. For this reason,
inhibition of the enzyme can alter those pathophysiological
conditions associated with a lowering cGMP level in tissues.
For example, selective PDE5 inhibitors, such as sildenafil
(Viagra, Pfizer), tadalafil (Cialis, Lilly-ICOS), and vardenafil
(Levitra, Bayer), have been successfully used to treat the
condition of human erectile dysfunction. More recently, the
involvement of this enzyme has been proposed to influence
antiproliferation and proapoptotic mechanism in multiple carcinomas.
The data supporting this idea is based on increases in PDE5
activities in many carcinomas and the ability of PDE5 inhibitors
such as exisulind and its analogs related to anticancer activities.
Inhibition of PDE5 that results in sustained increases in
[cGMP]i are required to modify the process of apoptosis and
mitotic arrest in those carcinoma cells with enhanced PDE5
expressions. Increases in PDE5 are also involved in contributing
to the pathological changes in the pulmonary system resulting
in hyper-proliferative remodeling of both smooth muscle and
endothelium in models of pulmonary hypertension. For this
reason, the use of PDE5 inhibitors in the treatment of human
pulmonary hypertension has met with some success. The differences
that we have previously noted in PDE isoenzymes in pulmonary
arterial and microvascular endothelial cells may provide a
more selective cellular strategy for use of such inhibitor.
Additional studies on structure biology of these enzymes should
lead to the development of agents with better cellular specificity
than currently available drugs. Considering the enormous progress
that has been made in the last few years, the future looks
promising for agents affecting this enzyme and related systems.
[Back to top]
Corrigendum
A significant portion of the manuscript of Loiseau, P. M.
and Bories C. entitled "Mechanisms of Drug Action and
Drug Resistance in Leishmania as Basis for Therapeutic Target
Identification and Design of Antileishmanial Modulators"
Curr. Top. Med. Chem. 2006, 6, 539-550
was copied verbatim from the paper of M. Ouellette, J. Drummelsmith,
and B. Papadopoulou entitled "Leishmaniasis: drugs in
the clinic, resistance and new developments" Drug
Res. Updates 2004, 7, 257-266. Therefore,
Curr. Top. Med. Chem. has formally retracted the
citation Loiseau, P. M.; Bories, C. Curr. Top. Med. Chem.
2006, 6, 539-550 from publication.
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