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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 8, 2006
Contents
Latest Developments in Pharmaceutical Design of Arachidonic
Acid Metabolites: Prostaglandins, Thromboxanes, Hepoxilins
and Isoprostanes
Executive Editors: J.-M. Dogné and K.-H.
Ruan
Editorial Pp. 893
The Isoprostanes - Unique Products of Arachidonate Peroxidation:
Their Role as Mediators of Oxidant Stress Pp. 895-902
J.D. Morrow
[Abstract]
From the Design to the Clinical Application of Thromboxane
Modulators Pp. 903-923
J.-M. Dogné, J. Hanson, X. de Leval,
D. Pratico, C.R. Pace-Asciak, P. Drion, B. Pirotte and K.-H.
Ruan
[Abstract]
Implications of the Molecular Basis of Prostacyclin Biosynthesis
and Signaling in Pharmaceutical Designs Pp. 925-941
K.-H. Ruan and J.-M. Dogné
[Abstract]
Prostaglandin E Synthase: A Novel Drug Target for Inflammation
and Cancer Pp. 943-954
M. Murakami and I. Kudo
[Abstract]
NAD+-Linked 15-Hydroxyprostaglandin Dehydrogenase:
Structure and Biological Functions Pp.955-962
H-H. Tai, H. Cho, M. Tong and Y. Ding
[Abstract]
Hepoxilin Analogs, Potential New Therapeutics in Disease
Pp. 963-969
C.R. Pace-Asciak, X. Li, N. Qiao, D. Reynaud, P. Demin
and M. Abdelhaleem
[Abstract]
Coxibs and Cardiovascular Side-Effects: From Light
to Shadow Pp. 971-975
J.-M. Dogné, J. Hanson, C. Supuran and D. Pratico
[Abstract]
General Articles
The Role of Unbound Drug in Pharmacokinetics/Pharmacodynamics
and in Therapy Pp. 977-987
R. Calvo, J.C. Lukas, M. Rodriguez, N. Leal and E. Suarez
[Abstract]
Biologicals Dramatic Advances in the Treatment of
Psoriasis Pp. 989-999
D. Wilsmann-Theis, S. Martin, M. Reber, B. Kwiek, T. Bieber
and N. Novak
[Abstract]
Role of Opioid Antagonists in the Treatment of Women with
Glucoregulation Abnormalities Pp. 1001-1012
M. Guido, D. Romualdi and A. Lanzone
[Abstract]
Abstracts
[Back
to top]
Editorial
In response to hormonal stimulation, phospholipases
are activated to release arachidonic acid from membrane phospholipids.
Free arachidonate can then metabolized nonenzymatically, contributing
to oxidative stress, or through the actions of different types
of oxygenase: cyclooxygenase (COX), lipoxygenase (LOX), and
cytochrome P450 monooxygenases. The arachidonic acid metabolites
produced, or eicosanoids, are a large series of lipid-derived
mediators capable of producing a multitude of physiologic
effects in the local environment. They play important roles
in a variety of signaling pathways both in physiologic and
pathophysiologic conditions. For many years, arachidonic acid
metabolism has become one of the most active area of fundamental
and applied research. Researchers and pharmaceutical companies
early focused their attention on new agents able to interfere
with metabolic steps in the degradation of arachidonic acid
or eicosanoid receptors. The aim of this hot topic is to highlight
the latest developments in the pharmaceutical design of some
specific arachidonic acid pathway metabolites or enzymes.
Thus, over a decade ago, Professor Jason D. Morrow reported
that a series of prostaglandin (PG)1-like compounds were produced
by the free radical-catalyzed peroxidation of arachidonic
acid, independent of the cyclooxygenase enzyme. Since then,
this researcher and others have accumulated a large body of
evidence indicating that quantification of these unique products
of lipid peroxidation, now termed isoprostanes, provides a
reliable marker of oxidant injury both in vitro and
in vivo. In the first review, the mechanisms involved
in isoprostanes formation, their biological activities at
a cellular level and the future research related to the development
of pharmacological approaches to modulate their formation
and action in vivo will be discussed [1]. Thromboxane
A2 (TXA2) and prostacyclin (PGI2)
are two key metabolites produced by the cyclooxygenase pathway
via thromboxane synthase and prostacyclin synthase,
respectively. TXA2 has been implicated in various
pathophysiological conditions due to its potent activating
effects on platelet aggregation and smooth muscle contraction.
In the second review of this hot topic, Dr. Jean-Michel Dogné,
co-guest editor, aims to describe the physiological properties
of TXA2, thromboxane synthase and thromboxane receptors
[2]. Two sections are dedicated to a presentation of each
class of TXA2 modulators with the advantages and
disadvantages they offer and to recent studies performed with
the most interesting TXA2 modulators in major pathologies
such as myocardial infarction and thrombosis, atherosclerosis,
diabetes, pulmonary embolism, septic shock, preeclampsia,
and asthma.
PGI2 is the main arachidonic acid
metabolite in vascular walls and has opposing biological properties
to TXA2. Indeed, PGI2 represents the
most potent endogenous inhibitor of platelet aggregation and
is also a strong anti-hypertensive agent through its vasodilatory
effects on vascular beds. Understanding the molecular mechanisms
of PGI2 biosynthesis and signaling is crucial to
the development of therapeutic approaches to regulate PGI2
functions. Thus, Dr. Ke-He Ruan, co-guest editor provides
information regarding the most current advances in the findings
of the molecular mechanisms for PGI2 biosynthesis
and for PGI2 signaling through its cell membrane
receptors and nuclear peroxisome proliferator-activated receptors
[3].
Prostaglandin E2 is the most common
prostanoid with a variety of bioactivities and has been implicated
in various pathologies. Prostaglandin E synthase (PGES), which
converts cyclooxygenase (COX)-derived prostaglandin H2
to PGE2, occurs in multiple forms with distinct
enzymatic properties, modes of expression, cellular and subcellular
localizations and intracellular functions. In their review,
Makoto Murakami and Dr. Ichiro Kudo highlight the latest understanding
of the expression, regulation and functions of these three
PGES enzymes, in particular mPGES-1 of which recent gene targeting
studies have revealed that this enzyme represents a novel
target for anti-inflammatory and anti-cancer drugs [4].
Prostaglandins, PGI2, TXA2
and lipoxins are rapidly metabolized by initial oxidation
of their 15(S)-hydroxyl group catalyzed by NAD+-linked
15-hydroxyprostaglandin dehydrogenase (15-PGDH). The 15-keto
products of this enzyme exhibit greatly reduced biological
activities. Therefore, this enzyme has been considered the
key enzyme responsible for the inactivation of these biologically
active eiocosanoids. Moreover, studies on the regulation of
enzyme expression and activity by physiological and pharmacological
agents have begun to uncover its significant roles in cancer,
inflammation and reproduction. In the fifth review, Dr. Hsin-Hsiung
Tai provides insight into structural characterization, transcriptional
regulation, biological functions and catalytic mechanism of
this enzyme [5].
In the sixth review, Professor Cecil Pace-Asciak
describes the results of his interesting studies with chemically
synthesized stable analogs (PBTs) of the naturally occurring
hepoxilins. These are produced through the isomerization of
12(S)-HPETE, a metabolite of arachidonic acid formed via
the 12(S)-lipoxygenase, via a putative hepoxilin
synthase. Some of the latest observations with the PBTs in
the areas of inflammation (inhibition of the bleomycin-evoked
lung fibrosis in mice in vivo), platelet aggregation
(antagonism of the thromboxane receptor in human platelets
in vitro) thrombosis (inhibitors in vivo),
and cancer (apoptosis of the human leukemia cell line, K562
in vitro and in vivo) are reviewed [6].
Finally, the last paper of this hot topic on
arachidonic acid metabolites will be dedicated to an overview
of the fate of COX-2 inhibitors. Indeed, the recent worldwide
withdraw of rofecoxib has raised serious concerns about safety
of this class of agents. A critical discussion of the latest
clinical, biochemical and pharmacological data on the “coxibs”
is proposed [7].
Last but not least, we want to thank all the
authors who kindly agreed to contribute to this hot topic.
We also want to thank the Manager of the publication of Current
Pharmaceutical Design for his patience and support in this
work.
References
[1] Morrow J. The Isoprostanes – Unique
Products of Arachidonate Peroxidation: Their Role as Mediators
of Oxidant Stress. Curr Pharm Design 2006; 12(8): 895-902.
[2] Dogné JM, Hanson J, de Leval X,
Pratico D, Pace-Asciak CR, Drion P, Pirotte B, Ruan KH. From
the Design to the clinical application of thromboxane modulators.
Curr Pharm Design 2006; 12(8): 903-923.
[3] Ruan KH, Dogné JM. Implications
of the Molecular Basis of Prostacyclin Biosynthesis and Signaling
in Pharmaceutical Designs. Curr Pharm Design 2006; 12(8):
925-941.
[4] Murakami I, Kudo I. Prostaglandin E synthase;
a novel drug target for inflammation and cancer. Curr Pharm
Design 2006; 12(8): 943-954.
[5] Tai HH, Cho H, Tong M, Ding Y. NAD+-linked
15-hydroxyprostaglandin dehydrogenase: structure and biological
functions. Curr Pharm Design 2006; 12(8): 955-962.
[6] Pace-Asciak CR, Li X, Qiao N, Reynaud D,
Demin P, Abdelhaleem M. Hepoxilin Analogs, potential new therapeutics
in disease. Curr Pharm Design 2006; 12(8): 963-969.
[7] Dogné JM, Hanson J, Supuran CT,
Pratico D. Coxibs and cardiovascular side-effects: from light
to shadow. Curr Pharm Design 2006; 12(8): 971-975.
Dr. Jean-Michel Dogné
Natural and Synthetic Drugs Research Center
The University of Liège
1, av. de l'Hopital, B36
B-4000 Liège, Belgium
E-mail: Jean-Michel.Dogne@ulg.ac.be
Dr. Ke-He Ruan
Vascular Biology Research Center and
Division of Hematology
Department of Internal Medicine
The University of Texas Health Science
Center, Houston, TX 77030, USA
E-mail: kruan@uth.tmc.edu
[Back to top]
The Isoprostanes - Unique Products of Arachidonate
Peroxidation: Their Role as Mediators of Oxidant Stress
J.D. Morrow
The isoprostanes (IsoPs) are a series of novel prostaglandin-like
compounds formed in vivo in humans from the free
radical-catalyzed peroxidation of arachidonate independent
of the cyclooxygenase. While quantification of these compounds
is a highly accurate measure of oxidant stress in vivo
in humans, IsoPs also possess potent biological activity and
likely mediate certain aspects of oxidative injury. The purpose
of this review is to summarize selected aspects of our knowledge
regarding the bioactivity of the IsoPs. I will first briefly
highlight mechanisms involved in IsoP formation. Subsequently,
I will discuss the biological activities of certain IsoPs
that are formed in abundance in vivo and focus on
two compounds, 15-F2t-IsoP and 15-E2t-IsoP,
that have been studied in the greatest detail. This review
will then examine, at a molecular level, mechanisms by which
IsoPs exert their bioactivity. It has been shown that they
are ligands for various eicosanoid receptors, in particular,
the thromboxane receptor. In addition, I will discuss the
controversial evidence that a unique IsoP receptor(s) exists.
Finally, I will offer avenues for future research related
to the development of pharmacological approaches to modulate
IsoP formation and action in vivo and thus decrease
the pathophysiological sequelae of oxidative injury.
[Back to top]
From the Design to the Clinical Application of Thromboxane
Modulators
J.-M. Dogné, J. Hanson, X. de Leval,
D. Pratico, C.R. Pace-Asciak, P. Drion, B. Pirotte and K.-H.
Ruan
Arachidonic acid (AA) metabolites are key mediators involved
in the pathogenesis of numerous cardiovascular, pulmonary,
inflammatory, and thromboembolic diseases. One of these bioactive
metabolites of particular importance is thromboxane A2
(TXA2). It is produced by the action of thromboxane
synthase on the prostaglandin endoperoxide H2 (PGH2)
which results from the enzymatic transformation of AA by the
cyclooxygenases. It is a potent inducer of platelet aggregation,
vasoconstriction and bronchoconstriction, and has been involved
in a series of major pathophysiological conditions. Therefore,
TXA2 receptor antagonists, thromboxane synthase
inhibitors and drugs combining both properties have been developed
by different laboratories since the early 1980s. Several compounds
have been launched on the market and others are under clinical
evaluation. In the first part of this review, we will describe
the physiological properties of TXA2, thromboxane
synthase and thromboxane receptors. The second part is dedicated
to a description of each class of thromboxane modulators with
the advantages and disadvantages they offer. In the third
part, we aim to describe recent studies performed with the
most interesting thromboxane modulators in major pathologies:
myocardial infarction and thrombosis, atherosclerosis, diabetes,
pulmonary embolism, septic shock, preeclampsia, and asthma.
Each pathology will be systematically reviewed. Finally, in
the last part we will highlight the latest perspectives in
drug design of thromboxane modulators and in their future
therapeutic applications such as cancer, metastasis and angiogenesis.
[Back to top]
Implications of the Molecular Basis of Prostacyclin
Biosynthesis and Signaling in Pharmaceutical Designs
K.-H. Ruan and J.-M. Dogné
Prostacyclin (PGI2) is one of the major vascular
protectors against thrombosis and vasoconstriction, caused
by thromboxane A2. Understanding the molecular
mechanisms of PGI2 biosynthesis and signaling is
crucial to the development of therapeutic approaches to regulate
PGI2 functions. This review provides information
regarding the most current advances in the findings of the
molecular mechanisms for PGI2 biosynthesis in the
endoplasmic reticulum (ER) membrane through the coordination
between PGI2 synthase and its upstream enzymes,
cyclooxygenase-1 (COX-1) or –2 (COX-2), and
for PGI2 signaling through its cell membrane receptors
and nuclear peroxisome proliferator-activated receptors. The
substrate presentation from the COXs to PGI2 synthase
and its cell membrane receptor/G protein coupling sites, as
characterized by our group, are discussed in detail. The association
between the regulation of the biosynthesis and signaling of
PGI2 with the pathophysiological processes of PGI2-related
diseases is also discussed. The molecular knowledge of PGI2
biosynthesis and signaling will help to design the next generation
of drugs, specifically targeting the regulation of PGI2
functions, which will undoubtedly provide advances in cardiovascular
protection and the treatment of PGI2-related diseases.
[Back to top]
Prostaglandin E Synthase: A Novel Drug Target for
Inflammation and Cancer
M. Murakami and I. Kudo
Prostaglandin E synthase (PGES), which converts cyclooxygenase
(COX)-derived prostaglandin (PG) H2 to PGE2,
occurs in multiple forms with distinct enzymatic properties,
modes of expression, cellular and subcellular localizations
and intracellular functions. Two of them are membrane-bound
enzymes and have been designated as mPGES-1 and mPGES-2. mPGES-1
is a perinuclear protein belonging to the MAPEG (for membrane-associated
proteins involved in eicosanoid and GSH metabolism) family.
This enzyme is markedly induced by proinflammatory stimuli,
is down-regulated by anti-inflammatory glucocorticoids, and
is functionally coupled with cyclooxygenase (COX)-2 in marked
preference to COX-1. mPGES-2 is synthesized as a Golgi membrane-associated
protein, and the proteolytic removal of the N-terminal hydrophobic
domain leads to the formation of a mature cytosolic enzyme.
This enzyme is rather constitutively expressed in various
cells and tissues and is functionally coupled with both COX-1
and COX-2. Cytosolic PGES (cPGES) is constitutively expressed
in a wide variety of cells and is functionally linked to COX-1
to promote immediate PGE2 production. This review
highlights the latest understanding of the expression, regulation
and functions of these three PGES enzymes. In particular,
recent gene targeting studies of mPGES-1 have revealed that
this enzyme represents a novel target for anti-inflammatory
and anti-cancer drugs.
[Back to top]
NAD+-Linked 15-Hydroxyprostaglandin Dehydrogenase:
Structure and Biological Functions
H-H. Tai, H. Cho, M. Tong and Y. Ding
NAD+-linked 15-hydroxyprostaglandin dehydrogenase
(15-PGDH) catalyzes the oxidation of 15(S)-hydroxyl group
of prostaglandins and lipoxins resulting in the formation
of 15-keto metabolites which exhibit greatly reduced biological
activities. Therefore, this enzyme has been considered the
key enzyme responsible for the inactivation of prostaglandins
and lipoxins. Both the cDNA and the genomic DNA of the 15-PGDH
gene have been cloned. Structural characterization, transcriptional
regulation and biological functions of this enzyme have been
investigated. Molecular modeling corroborated with site-directed
mutagenesis has identified key residues and domains involved
in coenzyme and substrate binding. Catalytic mechanism has
been proposed. Studies on the regulation of enzyme expression
and activity by physiological and pharmacological agents have
begun to uncover its significant roles in cancer, inflammation
and reproduction. Apparently, 15-PGDH works with cyclooxygenase-2
to control the cellular levels of prostaglandins. Their reciprocal
regulation within the same cells appears to determine the
fate of the cells. Because of its ability to inactivate both
prostaglandins and lipoxins of two opposite biological activities,
the roles of 15-PGDH in cancer and inflammation are particularly
intriguing and challenging. Future investigations in these
areas are warranted.
[Back to top]
Hepoxilin Analogs, Potential New Therapeutics in Disease
C.R. Pace-Asciak, X. Li, N. Qiao, D. Reynaud, P. Demin
and M. Abdelhaleem
We have chemically synthesized several stable analogs of
the naturally occurring hepoxilins, 12-LO products derived
from arachidonic acid, which we found to have promising actions
in a variety of test systems of disease. The analogs, PBTs,
afford chemical and biological stability to the hepoxilin
molecule. This article reviews some of our latest observations
with the PBTs in the areas of inflammation (inhibition of
the bleomycin-evoked lung fibrosis in mice in vivo),
platelet aggregation (antagonism of the thromboxane receptor
in human platelets in vitro) and thrombosis (inhibitors
in vivo), and cancer (apoptosis of the human leukemia
cell line, K562 in vitro and in vivo). The
demonstration that the PBTs are active in vivo suggests
that they can serve as a platform for their further development
as novel therapeutics in disease.
[Back to top]
Coxibs and Cardiovascular Side-Effects: From Light
to Shadow
J.-M. Dogné, J. Hanson, C. Supuran and D. Pratico
Since the discovery of COX-2, a second subtype of cyclooxygenase,
selective inhibitors or “coxibs” were developed
with the idea that this isoform was inducible at the site
of inflammation whereas COX-1 was expressed constitutively
in several tissues including gastric epithelium. This new
class of non steroidal anti-inflammatory agents was though
to be safer for ulcerations of the gastroinstestinal mucosa
observed with non selective COX-2 inhibitors. Nevertheless,
at the end of September 2004, Merck & Co announced the
voluntary withdrawal of rofecoxib (Vioxx) worldwide because
of an increased risk of cardiovascular events. This decision
raised serious concerns about safety of selective COX-2 inhibitors
which are actively marketed today, and the ones currently
under development. The mechanism of this cardiovascular toxicity
could lie in the inhibition of COX-2 itself, and thus be a
class effect. On the other hand, these cardiovascular side
effects could be limited on rofecoxib and be dependent on
its chemical and/or pharmacological own properties. This hypothesis
is undermined by the unexpected findings of one colon cancer
study which has shown that celecoxib might also increase the
chance of heart attack and stroke in some patients. In this
review, we compared the different coxibs marketed to date
on the basis of their clinical, pharmacological and chemical
properties with the aim of providing some clues in the understanding
of their potential or revealed “cardiovascular effects”.
[Back to top]
The Role of Unbound Drug in Pharmacokinetics/Pharmacodynamics
and in Therapy
R. Calvo, J.C. Lukas, M. Rodriguez, N. Leal and E. Suarez
The evolution of research on drug protein binding is discussed
with the unbound concentration (Cu) and the unbound fraction
(fu) as protagonists. Particular attention is paid to the
mechanisms via which alterations in binding affect
the pharmacokinetics (PK) and the effect, or independently
the pharmacodynamics (PD). Apart from albumin, the important
α-acid
glycoprotein (AGP), as well as specific drug classes and applications
in the clinic and development (routine monitoring, cancer
and HIV therapy, allometry) are addressed. The flaws with
the classical method of indirectly calculating the Cu or the
unbound PK/PD parameters, based on the fu in vitro,
are related to the intrinsic complexity and variability in
the outcomes. Increased focus is urged on directly estimating
the unbound PK/PD and also on using population statistical
methods.
[Back to top]
Biologicals Dramatic Advances in the Treatment of
Psoriasis
D. Wilsmann-Theis, S. Martin, M. Reber, B. Kwiek, T. Bieber
and N. Novak
Innovations in biotechnology have made possible the development
of several new systemic therapies for psoriasis - the "biologicals",
a new group of compounds including monoclonal antibodies,
fusion proteins and recombinant proteins. These novel biotechnological
advances potentially offer designer drugs, which interfere
with specific targets in the pathophysiological network of
psoriasis and are thus much safer. The therapeutic strategy
of biologicals is based on the knowledge derived from pathogenetic
studies, which have focused on targeting disease relevant
T-cell- or mediator-systems. Important targets include inactivation
of soluble mediators such as tumor-necrosis-factor-α,
the blockade of receptors for cytokines, adhesion molecules
and the interference with T-cell activation by antigen-presenting
cells. In addition, recombinant cytokines are able to modulate
the immunological balance of this chronic inflammatory skin
disease. Currently, up to forty agents are under investigation
for the treatment of psoriasis. Four of these agents, alefacept,
efali-zumab, etanercept and infliximab have already impacted
on routine clinical practice. Current developments in the
treatment of psoriasis with biologicals are reviewed.
[Back to top]
Role of Opioid Antagonists in the Treatment of Women with
Glucoregulation Abnormalities
M. Guido, D. Romualdi and A. Lanzone
Beta-endorphin were detected in the endocrine pancreas and
seem able to influence insulin and glucagon release. Hence,
endogenous opioids could have a role in glucoregulation and
in the pathogenesis of obesity beyond the previously detected
effects on appetite.
Metabolic abnormalities, such as hyperinsulinemia, insulin-resistance
and obesity, are common features of polycystic ovary syndrome
(PCOS), and seem to have a pathogenetic role in this disorder.
A link between opioids and PCOS-related hyperinsulinism is
suggested by the finding of altered central opioid tone and
elevated β-endorphins
levels, directly correlated with body weight, in these patients.
Furthermore, naloxone and naltrexone significantly reduce
the insulin response to glucose load only in hyperinsulinemic
PCOS patients. This effect is obtained chiefly through an
improvement of insulin clearance. Naltrexone is also able
to ameliorate the abnormal gonadotrophins secretion and to
improve the ovarian responsiveness in obese PCOS women undergoing
ovulation induction with exogenous GnRH. Such effects are
believed to be obtained through an amelioration of hyperinsulinemia.
Gonadal steroids modulate the opioid system both centrally
and in peripheral districts. Nevertheless, the decline of
ovarian function does not abolish the opioidergic control
of glucoregulation.
Post-menopausal period is characterised by a high prevalence
of hyperinsulinemia and insulin-resistance. In particular,
an association between hyperinsulinemia and increased opioid
activity was found in postmenopausal women showing a central
body fat distribution. Both naloxone and naltrexone ameliorate
the metabolic imbalance also when it appears in the climacteric
period, and mainly by increasing insulin clearance. The benefits
of naltrexone may represent in the future a useful tool for
the treatment of women with hyperinsulinism in the clinical
practice.
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