| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 16, Number 33, 2009
Contents
Cholesterol Ester Transfer Protein (CETP), Postprandial Lipemia
and Hypolipidemic Drugs Pp. 4345-4360
G.D. Kolovou, K.K. Anagnostopoulou, P.M. Kostakou
and D.P. Mikhailidis
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Article]
Liposome-Encapsulated Anticancer Drugs: Still Waiting
for the Magic Bullet? Pp. 4361-4373
R. Fanciullino and J. Ciccolini
[Abstract] [Purchase
Article]
Chemogenomic Strategies to Expand the Bioactive
Chemical Space Pp. 4374-4381
E. Jacoby and A. Mozzarelli
[Abstract] [Purchase
Article]
Inhibition of Mitochondrial Membrane
Permeability as a Putative Pharmacological Target for Cardioprotection
Pp. 4382-4398
D. Morin, R. Assaly, S. Paradis and A. Berdeaux
[Abstract] [Purchase
Article]
The Medicinal Chemistry of Peptides Pp. 4399-4418
J.J. Nestor, Jr.
[Abstract] [Purchase
Article]
Protein Cysteine Modifications: (1) Medical Chemistry
for Proteomics Pp. 4419-4444
N. Nagahara, T. Matsumura, R. Okamoto and Y. Kajihara
[Abstract] [Purchase
Article]
Radiolabelled Oligonucleotides for Imaging of Gene
Expression with PET Pp. 4445-4461
G. Lendvai, S. Estrada, and M. Bergström
[Abstract] [Purchase
Article]
Pituitary Adenylate Cyclase-Activating Polypeptide:
Focus on Structure-Activity Relationships of a Neuroprotective
Peptide Pp. 4462-4480
S. Bourgault, D. Vaudry, A. Dejda, N.D. Doan, H. Vaudry
and A. Fournier
[Abstract] [Purchase
Article]
The Design and Development of Fesoterodine as a Prodrug
of 5-Hydroxymethyl Tolterodine (5-HMT), the Active Metabolite
of Tolterodine Pp. 4481-4489
B. Malhotra, K. Gandelman, R. Sachse, N. Wood and
M.C. Michel
[Abstract] [Purchase
Article]
Abstracts
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Cholesterol Ester Transfer Protein (CETP), Postprandial Lipemia
and Hypolipidemic Drugs
G.D. Kolovou, K.K. Anagnostopoulou, P.M. Kostakou
and D.P. Mikhailidis
Cholesterol ester transfer protein (CETP) plays a significant
role in high density lipoprotein (HDL) metabolism and reverse
cholesterol transport (RCT). A reduction in CETP activity
leads to an increase in HDL-cholesterol levels. However, the
relationship between reduced CETP function and atherosclerosis
is complex and confusing. In the hypertriglyceridemic state,
CETP is highly expressed and RCT leads to the formation of
small dense low density lipoprotein (LDL) and small dense
HDL, both of which are involved in the progression of atherosclerosis.
Significant associations of the B1B1 genotype with higher
plasma CETP concentration and/or CETP activity and lower HDL
cholesterol were reported in several, but not all, studies.
The magnitude of postprandial lipemia is also associated with
plasma CETP concentration and lipoprotein content and size.
Several conditions such as metabolic syndrome, hypertension,
insulin resistance, obesity and familial hypercholesterolaemia
are characterized by a more pronounced postprandial hypertriglyceridemia
and delayed TG clearance than normal states. Thus, CETP is
considered as a candidate target for drug therapy.
A number of synthetic CETP inhibitors (CGS25159 and JTT-705)
were evaluated in animals with satisfactory results. In humans,
two CETP inhibitors were evaluated, JTT-705 and torcetrapib,
leading to HDL increase. However, torcetrapib administration
was associated with an increase in blood pressure and other
“off-target” effects. It is also not clear whether
the HDL produced during treatment with torcetrapib is bioactive
(i.e. an “on target” undesirable action). In the
current review, CETP function regarding lipid metabolism (in
fasting and fed states) from human and animal studies as well
as the current knowledge on CETP inhibitors are discussed.
We also discuss gender influence on the action of hypolipidemic
drugs and their effect on CETP mass and activity, as well
as on the lipid profile.
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Liposome-Encapsulated Anticancer Drugs: Still Waiting
for the Magic Bullet?
R. Fanciullino and J. Ciccolini
Anticancer drugs are essential agents in the global strategy
developed to fight cancer. Still, narrow therapeutic indices,
erratic pharmacokinetics profiles and lack of selectivity
towards malignant tissues often hamper their efficacy at the
bedside, when they not cause severe toxicities. In this respect,
developing innovative drug delivery strategies that would
selectively target malignant tissues is still an ongoing story,
both in experimental and in clinical oncology. Delivery systems
such as liposomes are usually required when an existing formulation
is not satisfactory, because encapsulation is expected to
provide higher therapeutic efficacy and safety. Such significant
improvement in therapeutic efficacy and/or therapeutic indices
has already been achieved in patients with some liposome-encapsulated
drugs such as anthracyclines. It is now possible to develop
a wide range of vectors varying in size, composition, and
surface morphology suitable for a variety of therapeutic applications,
including for targeting tumor tissues. Reformulation of anticancer
drugs in liposomes remains a challenging opportunity to stretch
the therapeutic indices of many cytotoxic drugs, through the
optimization of their distribution in the body. Despite these
promising and exciting perspectives in oncology, to date only
few drugs (e.g., anthracyclines) have actually made their
way as liposomes from the bench to the bedside. However, as
target therapies have brought a new hope in the cancer war
in the 2000’s, developing now targeted delivery systems
is more and more seen as the next step to further improve
clinical outcome in cancer patients. This review covers the
achievements, limits, and new expectancies of anticancer drugs
as candidates for liposomal encapsulation.
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Chemogenomic Strategies to Expand the Bioactive
Chemical Space
E. Jacoby and A. Mozzarelli
Chemogenomics aims towards the systematic identification
of small molecules that interact with the products of the
genome and modulate their biological function. The establishment
and expansion of a comprehensive ligand-target Structure-Activity
Relationship matrix is following the elucidation of the human
genome a key scientific challenge for the 21st
century. Small chemical compounds are the first dimension
of the ligand-target SAR matrix. Accordingly, the systematic
expansion of the physically available and bioactive chemical
space is a key objective of chemogenomics. The vital question
is, how to enlarge the physically existing chemical space
into the bioactive and drug-like spaces? Effective systematic
expansion of the chemical space to reach a maximum of biological
binding sites appears possible when conserved molecular recognition
principles are the founding hypothesis for the design of the
compounds. Such principles, including approaches focusing
on target families, privileged scaffolds, protein secondary
structure mimetics, co-factor mimetics, and DOS and BIOS libraries
are summarized in this mini-review article.
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Inhibition of Mitochondrial Membrane Permeability
as a Putative Pharmacological Target for Cardioprotection
D. Morin, R. Assaly, S. Paradis and A. Berdeaux
Myocardial ischemia-reperfusion injury is a major cause of
morbidity and mortality in developed countries. To date, the
only treatment of complete ischemia is to restore blood flow;
thus the search for new cardioprotective approaches is absolutely
necessary to reduce the mortality associated with myocardial
ischemia.
Ischemia has long been considered to result in necrotic tissue
damage but the reduction in oxygen supply can also lead to
apoptosis. Therefore, in the last few years, mitochondria
have become the subject of growing interest in myocardial
ischemia-reperfusion since they are strongly involved in the
regulation of the apoptotic process. Indeed, during ischemia-reperfusion,
pathological signals converge in the mitochondria to induce
permeabilization of the mitochondrial membrane. Two classes
of mechanisms, which are not mutually exclusive, emerged to
explain mitochondrial membrane permeabilization. The first
occurs via a non-specific channel known as the mitochondrial
permeability transition pore (mPTP) in the inner and the outer
membranes causing disruption of the impermeability of the
inner membrane, and ultimately complete inhibition of mitochondrial
function. The second mechanism, involving only the outer membrane,
induces the release of cell death effectors. Thus, drugs able
to block or to limit mitochondrial membrane permeabilization
may be cytoprotective during ischemia-reperfusion. The objective
of this review is to examine the pharmacological strategies
capable of inhibiting mitochondrial membrane permeabilization
induced by myocardial ischemia-reperfusion.
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The Medicinal Chemistry of Peptides
J.J. Nestor, Jr.
The shortcomings of native peptides as pharmaceuticals have
been long known: short duration of action, lack of receptor
selectivity, lack of oral bioavailability. However medicinal
chemistry offers solutions to the first two limitations and
oral bioavailability issues have been addressed with novel
routes of administration (e.g. intranasal, inhalation) and
injectable depot formulations. The principal issue for peptide
drugs has been a short duration of action, widely assumed
to be due to proteolysis. While proteolysis is a problem for
native peptide structures, modification of the peptide structure
by acylation, PEGylation, unnatural amino acids or restricted
conformation can largely remove this issue. However rapid
clearance from the blood into the urine remains an issue for
even proteolytically stable molecules. Medicinal chemistry
approaches here have been peptide modifications to slow release
from the injection site (hydrophobic, hydrophilic, self-associating
depots), PEGylation, fatty acid acylation, and the like. Medicinal
chemistry approaches used in successful peptide pharmaceuticals
using unnatural amino acids to achieve depot formation are
highlighted in this review.
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Protein Cysteine Modifications: (1) Medical Chemistry
for Proteomics
N. Nagahara, T. Matsumura, R. Okamoto and Y. Kajihara
Protein cysteines (cysteinyl residues) play critical roles
in biological processes. In the course of protein evolution
under oxidizing atmosphere of the Earth, organisms have utilized
highly reactive cysteines in many proteins essential for maintenance
of life, i.e. enzymes, transcriptional factors, cytoskeletons,
and receptors. In some enzymes, sophistical cysteine modification
characterizes each catalytic mechanism. In vivo modification
of protein cysteines with natural chemical compounds modulates
protein functions as a molecular switch. Oxidation/reduction,
thiol-disulfide exchange, nitrosylation, sulfuration, thiolation,
acylation and prenylation are involved. Some protein cysteines
coordinate metals or metal cofactors such as a heme or an
iron sulfur cluster to form metalloproteins, serving as sensor
proteins, metalloenzymes or transcriptional factors. Information
on the in vitro chemical modifications and their
reaction specificities of protein cysteines are essential
for the investigation of the mechanisms and functions of in
vivo protein cysteine modifications. In this review,
we also mention historically important knowledge other than
recent results on protein cysteine modification and modulation
of protein function to fertilize medical proteomics.
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Radiolabelled Oligonucleotides for Imaging of Gene
Expression with PET
G. Lendvai, S. Estrada, and M. Bergström
Our understanding of altered patterns of gene expression being
responsible for many diseases has been growing thanks to modern
molecular biological methods. Today, these changes can only
be identified when tissue samples are available. Therefore,
a noninvasive method allowing us to monitor gene expression
in vivo would be valuable, not only as a research
tool, but also for patient stratification before treatment
and for treatment follow-up.
Antisense oligonucleotides (ODN) have been considered to be
suitable molecules to trace active genes in vivo,
as well as to treat diseases by hybridising to its complementary
messenger RNA (mRNA) sequence in the cells thereby preventing
the synthesis of the peptide. However, the use of ODNs in
the organisms are endangered by many hurdles such as physical
barriers to pass and enzyme attack to be avoided. Positron
emission tomography (PET) provides a most advanced in
vivo imaging technology that allows the exploration of
the fate of radionuclide-labelled antisense ODNs in the body;
thereby providing information about biodistribution and quantitative
accumulation in tissues to assess pharmacokinetic properties
of ODNs. This kind of evaluation is important as part of the
characterisation of antisense therapeutics but also as part
of the development of antisense imaging agents.
This review provides a general summary about the antisense
concept and displays the present status of the antisense imaging
field with the major achievements and remaining challenges
on the long journey towards accomplishing in vivo
monitoring of gene expression using PET.
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Pituitary Adenylate Cyclase-Activating Polypeptide:
Focus on Structure-Activity Relationships of a Neuroprotective
Peptide
S. Bourgault, D. Vaudry, A. Dejda, N.D. Doan, H. Vaudry
and A. Fournier
Pituitary adenylate cyclase-activating polypeptide (PACAP)
is a 38-amino acid peptide that was initially isolated from
hypothalamus extracts on the basis of its ability to stimulate
the production of cAMP in cultured pituitary cells. Recent
studies have shown that PACAP exerts potent neuroprotective
effects not only in vitro but also in in vivo
models of Parkinson’s disease, Huntington’s disease,
traumatic brain injury and stroke. The protective effects
of PACAP are based on its capacity to prevent neuronal apoptosis
by acting directly on neurons or indirectly through the release
of neuroprotective factors by astrocytes. These biological
activities are mainly mediated through activation of the PAC1
receptor which is currently considered as a potential target
for the treatment of neurodegenerative diseases. However,
the use of native PACAP, the endogenous ligand of PAC1, as
an efficient neuroprotective drug is actually limited by its
rapid degradation. Moreover, injection of PACAP to human induces
peripheral side effects which are mainly mediated through
VPAC1 and VPAC2 receptors. Strategies to overcome these compromising
conditions include the development of metabolically stable
analogs of PACAP acting as selective agonists of the PAC1
receptor. This review presents an overview of the structure-activity
relationships of PACAP and summarizes the molecular and conformational
requirements for activation of PAC1 receptor. The applicability
of PACAP analogs as therapeutic agents for treatment of neurodegenerative
diseases is also discussed.
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The Design and Development of Fesoterodine as a Prodrug
of 5-Hydroxymethyl Tolterodine (5-HMT), the Active Metabolite
of Tolterodine
B. Malhotra, K. Gandelman, R. Sachse, N. Wood and
M.C. Michel
This review highlights the design and development of fesoterodine
(Toviaz®)
as a prodrug of 5-hydroxymethyl tolterodine (5-HMT),
which is also the active metabolite of tolterodine, for the
treatment of overactive bladder (OAB). Tolterodine and 5-HMT
are both potent antimuscarinic agents. A prodrug approach
was necessary for systemic bioavailability of 5-HMT after
oral administration. Fesoterodine was selected amongst a series
of ester analogues of 5-HMT to develop an advanced OAB treatment
with an optimum biopharmaceutics profile, while maintaining
a pharmacological link to tolterodine.
While tolterodine and 5-HMT have similar antimuscarinic activity,
the logD value, a determinant of lipophilicity and per-meability
across biological interfaces such as the gut wall and blood-brain
barrier, is considerably lower for 5-HMT (0.74) versus tolterodine
(1.83). In contrast to the cytochrome P450 (CYP) 2D6-mediated
metabolism of tolterodine, 5-HMT formation from fesoterodine
occurs via ubiquitous nonspecific esterases. Consequently,
treatment with fesoterodine results in consistent, genotype-independent
exposure to a singular active moiety (5-HMT); treatment with
tolterodine results in CYP2D6 genotype-dependent exposure
to varying proportions of two active moieties (5-HMT and tolterodine).
At least partially due to the avoidance of variations in pharmacokinetic
exposures observed with tolterodine, it was possible to de-velop
fesoterodine with the flexibility of two efficacious and well-tolerated
dosage regimens of 4 and 8 mg daily.
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