Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 7, Number 3, 2007
Contents
Anti-Inflammatory Therapy
Guest Editor: Dr. Subhash P. Khanapure
Editorial Pp. 233-234
COX-2 Inhibitors Celecoxib and Parecoxib:
Valuable Options for Postoperative Pain Management
Pp. 235-249
Noor M. Gajraj
[Abstract]
Licofelone-A Novel Analgesic and Anti-Inflammatory
Agent Pp. 251-263
S. K. Kulkarni and Vijay Pal Singh
[Abstract]
Dual Acting Anti-Inflammatory Drugs Pp. 265-275
S. Leone, A. Ottani and A. Bertolini
[Abstract]
Cyclo-Oxygenase (COX) Inhibiting Nitric Oxide Donating
(CINODs) Drugs: A Review of Their Current Status
Pp. 277-282
Fiorucci Stefano and Eleonora Distrutti
[Abstract]
COX-2/5-LOX Dual Acting Anti-Inflammatory Drugs in
Cancer Chemotherapy Pp. 283-296
Laurence Goossens, Nicole Pommery and Jean Pierre Hénichart
[Abstract]
New Approaches to the Modulation of the Cyclooxygenase-2
and 5-Lipoxygenase Pathways Pp. 297-309
A. González-Périz and J. Clària
[Abstract]
Eicosanoids in Inflammation: Biosynthesis, Pharmacology,
and Therapeutic Frontiers Pp. 311-340
Subhash P. Khanapure, David S. Garvey, David R. Janero
and L. Gordon Letts
[Abstract]
Abstracts
[Back to top]
Editorial
Significant advances for treating the signs and symptoms
of inflammatory disease have been made in the last decade.
Most of the existing anti-inflammatory drugs are effective,
but not without adverse effects. Various strategies have been
employed to overcome the major problem of the gastrointestinal
(GI) toxicity that may accompany the long-term use of the
traditional nonsteroidal anti-inflammatory drugs (NSAIDs).
Among the most high-profile of these strategies in recent
years has been the development of cyclooxygenase-2 (COX-2)
selective inhibitors.
The discovery of COX-2 identified an enzyme that is specifically
upregulated during inflammation to produce pro-inflammatory
prostaglandins (PGs). Selective COX-2 inhibition was thus
embraced by many pharmaceutical companies as a major therapeutic
and commercial goal predicated upon the “COX-2 hypothesis”:
selective COX-2 inhibition should obviate the GI toxicity
of nonselective NSAIDs by blocking selectively pro-inflammatory
PG synthesis at inflammatory sites without interfering with
gastroprotective PG production by cyclooxygenase-1 (COX-1)
in the GI tract. Over the last fifteen years, remarkable accomplishments
have been made on the synthesis of structurally diverse COXIBs,
the identification of COXIBs with attractive preclinical profiles,
and COXIB clinical development and marketing. As anti-inflammatory
medicines, COXIBs proved just as effective as classical NSAIDs,
but with reduced GI side-effects and notably better GI tolerability.
By 2001, COXIBs had established a virtually unprecedented
record in the pharmaceutical industry for global sales growth,
sustained by an aggressive marketing program focused on COXIB
GI safety.
Since highly selective COX-2 inhibitors attenuate production
of prostacyclin (PGI2), an important anti-thrombotic eicosanoid,
theoretical concerns were voiced as early as 1999-2001 about
their potential to precipitate cardiovascular events. In September,
2004, Merck voluntarily withdrew rofecoxib from the market
in the face of clinical data from the APPROVe trial showing
that subjects who had taken 25 mg rofecoxib/day for more than
18 months had a four-fold greater incidence of serious thromboembolic
events and a doubling of the myocardial infarction rate vs.
the placebo group. Subsequent reports provided compelling
clinical evidence that structurally diverse COXIBs carry an
enhanced cardiovascular risk that is likely a dose-dependent
class effect, especially for patients already at moderate-to-high
risk of cardiovascular disease. Although in February, 2005,
an FDA panel reviewed the cardiovascular safety of COXIBs
and voted to allow their continued use, in April of that year
the FDA requested withdrawal of valdecoxib (and its intravenously
administered prodrug, parecoxib) from the market due to a
cluster of cardiovascular events in treated patients undergoing
coronary bypass graft surgery. The COXIB trajectory as a parabola
spanning almost a decade stands as one of the biggest disappointments
in the pharmaceutical industry and invites new thinking and
approaches.
In this issue, recent developments in anti-inflammatory drug
development as well as possible future strategies have been
reviewed.
The status of currently available COX-2 inhibitor “Celecoxib”
and its safety are presented in detail in the first contribution.
Gajraj gives an outstanding in-depth overview of COX-2 inhibitors
celecoxib and parecoxib as valuable options for post-operative
pain management.
Kulkarni and Singh describe “Licofelone a novel dual
acting COX/5-LOX inhibitor” in the second contribution
and give an up-to-date overview that covers our contemporary
understanding of pathogenic mechanisms in inflammatory conditions,
NSAID-induced adverse GI effects, and the rationale for the
development of “Licofelone” (a dual 5-LOX/COX
inhibitor) with data on its in vivo efficacy, pharmacodynamic
activity, clinical studies, and comparison with COX-2 selective
and nonselective inhibitors.
The third contribution describes the development of dual acting
anti-inflammatory drugs and the rationale for the development
of dual acting drugs. Leone, Ottani and Bertolini gave an
interesting overview of this topic, which also includes 5-LO
expression and implication of 5-LO derived leukotrienes (LTs)
in atherosclerosis and cardiovascular inflammation, an area
that is currently receiving considerable attention.
As alternatives to highly-selective COX-2 inhibitors, COX
inhibiting nitric oxide (NO) donating drugs (CINODs) (previously
termed “NO-NSAIDs”) have attracted interest. Nitroalkoxy
esters of traditional NSAIDs are pro-drugs that are hydrolyzed
to the parent NSAID and the nitroalkoxy ester. The nitroalkoxy
ester can produce NO, presumably by physiological routes of
reductive organic nitrate metabolism. The NO produced protects
the gastric mucosa from vascular injury and the adverse effects
of leukocytes that are infiltrated due to COX-1 inhibition.
The fourth contribution by Fiorucci, Elisabetta, and Eleonora
reviews the CINOD area. The rationale for developing nitric
oxide donating NSAIDs, their beneficial gastrointestinal profile,
and their current clinical status are described in detail.
Although the once aggressive pursuit by the pharmaceutical
industry of COX-2 selective inhibitors as anti-inflammatory
agents has been quelled by an associated, apparently class-effect
cardiovascular risk, their therapeutic potential has not been
negated. For example, COX-2 selective inhibitors possess anti-cancer
properties, at least some of which may reflect the involvement
of COX-2-derived PGs in promoting the disease. Fifth and sixth
contributions detail recent developments in the use of dual
acting anti-inflammatory drugs in cancer chemotherapy. The
involvement of LTs has also been recognized in cancer such
that dual COX-2/5-LO inhibitors could be very promising anti-cancer
drugs. An interesting review by Goossens, Pommery, and Henichart
highlights the potential use of COX-2/5-LO dual-acting drugs
which could be a valid approach to more effective anti-cancer
drugs in cancer chemotherapy and also covers the synthetic
strategies and novel templates explored for the development
of dual acting COX-2/5-LO inhibitors.
Gonzalez-Periz and Claria reviewed new approaches in the modulation
of COX-2 and 5-LO pathways as a promising targets for developing
"COX-2/5-LO" dual-acting anti-cancer drugs that
may offer the added benefit of pain management in cancer patients.
Their coverage of receptor-mediated biological effects of
PGs, activation of PPARs, and the involvement of COX-2 derived
PGs in promoting the disease by stimulation of cell proliferation
and angiogenesis is very impressive.
Finally, in the last contribution we have reviewed recent
developments in the discoveries of new biochemical pathways,
identification of new pro-inflammatory mediators and their
receptor mediated mechanisms in inflammatory conditions. An
update on COX-2 inhibitors, 5-LO inhibitors, leukotriene D4
antagonists, clinical update on MAP kinase p38α
inhibitors, and the mechanisms involved in the beneficial
effects of omega-3 fatty acids to prevent chronic inflammation
are also reviewed.
As a guest editor, I am most grateful to all the authors for
contributing to this special issue. I wish to express my appreciation
to them for their outstanding and timely reviews.
Subhash P. Khanapure
NitroMed, Inc.,
125 Spring Street,
Lexington,
Massachusetts 02421,
USA
[Back to top]
COX-2 Inhibitors Celecoxib and Parecoxib: Valuable
Options for Postoperative Pain Management
Noor M. Gajraj
COX-2 inhibitors are equally as efficacious as the non-selective
NSAIDs for the treatment of postoperative pain, but have the
advantages of a better gastrointestinal side-effect profile
as well as a lack of antiplatelet effects. There have been
recent concerns regarding the cardiovascular side effects
of COX-2 inhibitors. Nonetheless, they remain a valuable option
for postoperative pain management. The pharmacology of these
agents and available studies are reviewed.
[Back to top]
Licofelone-A Novel Analgesic and Anti-Inflammatory
Agent
S. K. Kulkarni and Vijay Pal Singh
Dual inhibitors that block both cyclooxygenase (COX) and lipoxygenase
(LOX) metabolic pathways of arachidonic acid are expected
to possess clinical advantages over the selective inhibitors
of COX enzyme. One of the most promising compounds belonging
to this category is licofelone ([2,2 –dimethyl –6-(4-chloropheny-7-phenyl-2,3-dihydro-1H-pyrrazoline-5-yl]
acetic acid). Originally discovered by Merckle GmbH and developed
by EuroAllaince, licofelone (IC50 COX=0.21 μM,
IC50 5-LOX=0.18μM)
possesses significant analgesic, anti-inflammatory, and antiasthmatic
effects at doses that cause no gastrointestinal (GI) side
effects. The pharmacodynamic profile of licofelone has been
assessed and compared with widely used NSAIDs in different
animal models. The ED50 value of licofelone is
reported to be 11.22-27.07 mg/kg, po and 39.5-55-8 mg/kg,
po against carrageenan-induced paw oedema and Randal Selitto
hyperalgesic assay in rats, respectively. Licofelone showed
analgesic effect (ED50 = 31.33 mg/kg) against acetic
acid-induced writhing in mice. Licofelone has long duration
of action and more effective than indomethacin and zileuton
with ED50 values of 2.92 mg/kg, po and 36.77 mg/kg,
po, in the mechanical hyperalgesia and cold allodynia testing,
respectively, against rat model of incisional pain. Licofelone
significantly ameliorated indomethacin-induced gastric ulceration,
neutrophil adhesion in mesentery, and lipid peroxides in rat
gastric mucosa. Also, licofelone reversed the altered vascular
permeability, morphological changes, and prevented NSAIDs-related
increase in leukotriene levels in gastric mucosa.
The preclinical studies have shown that licofelone not only
has convincing pharmacodynamic effect but also it is well
tolerated. It is currently under clinical evaluation in osteoarthritis
(OA), the most common form of arthritis. The present review
describes pharmacological and clinical development of licofelone
as a dual inhibitor.
[Back to top]
Dual Acting Anti-Inflammatory Drugs
S. Leone, A. Ottani and A. Bertolini
Drugs able to inhibit both cyclooxygenases (COX-1 and COX-2)
and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory
drugs) have been designed in order to obtain compounds that
retain the activity of classical nonsteroidal anti-inflammatory
drugs (NSAIDs) while avoiding their main drawbacks. The classical
NSAIDs display their anti-inflammatory action mainly through
inhibition of COX and one of their main drawbacks is the curtailed
production of gastroprotective prostaglandins (PGs) being
associated with the concurrent increased production of the
gastro-damaging and bronchoconstrictive leukotrienes (LTs).
Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory
and increase microvascular permeability. One of the leukotrienes
(LTB4) is the most potent chemotactic agent and
it induces chemotaxis of eosinophils, neutrophils and monocytes
in the inflamed tissue, increases superoxide generation and
proinflammatory cytokines production. It is further advantageous
for a drug to have both COX and 5-LOX inhibiting activities
because prostaglandins enhance leukotriene-mediated inflammation.
Various structural families of dual inhibitors have been designed
and several compounds are currently undergoing clinical development.
In the post-COX-2 selective inhibitors era, these dual acting
inhibitors may turn out to be promising new drugs to treat
inflammatory diseases and possibly other diseases. Indeed,
both COX-2 and 5-LOX are also involved in the development
and progression of several types of cancer; in these conditions,
selective inhibition of COX-2 alone may lead to a shunt of
arachidonic acid metabolism towards the leukotriene pathway,
and therefore the blockade of both COX-2 and 5-LOX may produce
a better anticancer response. In addition, the dual inhibition
of both COX and 5-LOX is neuroprotective by suppressing toxic
actions of reactive microglia and macrophages, that are increased
in aging brain and in age-related degenerative conditions,
particularly Alzheimer’s and Parkinson’s diseases.
Finally, the blockade of 5-LOX does not impair the synthesis
of lipoxins (LXs), which are mainly produced by further lipoxygenation
of 15-HPETE, and which have potent anti-inflammatory properties
and can be considered as stop-signal mediators. Leukocyte
15-LOX and platelet 12-LOX by intercellular mechanism via
leukocyte/platelet cell-cell interaction convert 15-HPETE
into lipoxins.
[Back to top]
Cyclo-Oxygenase (COX) Inhibiting Nitric Oxide Donating
(CINODs) Drugs: A Review of Their Current Status
Fiorucci Stefano and Eleonora Distrutti
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely
used drugs but their use is hampered by gastrointestinal side
effects. Cyclo-oxygenase Inhibitor Nitric Oxide Donors (CINODs)
are a new class of anti-inflammatory and analgesic drugs generated
by adding a nitric oxide generating moiety to the parent NSAID
via an ester linkage. The combination of balanced inhibition
of the two main COX isoforms with release of NO confers to
CINODs a reduced gastrointestinal toxicity and a potent anti-inflammatory
activity. It is suggested that the NO, which is released by
the metabolism of nitrate as the compounds are broken down,
may counteract the consequences of the NSAID-induced decrease
in gastric mucosal prostaglandins. Recent clinical trials
with CINODs (previously termed NO-NSAIDs) have provided data
consistent with pre-clinical observations.
[Back to top]
COX-2/5-LOX Dual Acting Anti-Inflammatory Drugs in
Cancer Chemotherapy
Laurence Goossens, Nicole Pommery and Jean Pierre Hénichart
Emerging reports now indicate alterations of arachidonic acid
metabolism with carcinogenesis and many COX and LOX inhibitors
(used for the treatment of inflammatory diseases) are being
investigated as potential anticancer drugs. Results from clinical
trials seem to be encouraging but a better knowledge of the
dynamic balance that shifts toward lipoxygenases (and different
isoforms of LOXs) and cyclooxygenase-2 are essential to progress
in the design of new drugs more specially directed on chemoprevention
or chemotherapy of human cancers. So, on the basis of these
results, it seemed useful to study the advantages of combination
of COX inhibitor with LOX inhibitor and a next step will be
the conception of dual inhibitors able to induce the anticarcinogenic
and/or to inhibit the procarcinogenic enzymes responsible
for polyunsaturated fatty acid metabolism. After a rapid summary
of some recent reviews published on the involvement of different
COX and LOX isoforms present in human cells, we will discuss
on cross-talk reported between the downstream pathways which
contribute to the development and progression of human cancers.
This will lead us to evoke and to justify alternative strategies
to develop agents that modulate multiple targets simultaneously
with the aim of enhancing efficacy or improving safety relative
to drugs that address only a single enzyme.
[Back to top]
New Approaches to the Modulation of the Cyclooxygenase-2
and 5-Lipoxygenase Pathways
A. González-Périz and J. Clària
The eicosanoid family comprises a number of biologically active
lipid mediators involved in the regulation of inflammation
and cancer cell growth. Eicosanoid biosynthesis is usually
initiated by the release of arachidonic acid (AA) from membrane
phospholipids in response to the interaction of a phospholipase-A2
(PLA2) stimulus with a receptor on the cell membrane.
The free released AA is subsequently metabolized by three
major enzymatic pathways: the cyclooxygenase (COX), lipoxygenase
(LO) and cytochrome P450-dependent pathways. The COX pathway
transforms AA into prostaglandins (PGs) and is of particular
clinical relevance because it is the main target for non-steroidal
anti-inflammatory drugs (NSAIDs). Of interest, COX-2, one
of the two COX isoforms, is primarily involved in inflammation
and cancer and for this reason selective COX-2 inhibitors
have been developed. The efficacy of these compounds is similar
to that of traditional NSAIDs but with a lower risk of gastrointestinal
toxicity and bleeding. On the other hand, emerging information
has recognized the role of other AA metabolites derived from
the 5-LO pathway, the leukotrienes (LTs), in mediating and
maintaining inflammation. Consequently, drugs able to inhibit
5-LO are now included among the effective pharmacological
therapies, especially in asthma and allergic inflammation.
Moreover, COX-2 and 5-LO pathways appear to act in parallel
in the regulation of cell proliferation and neo-angiogenesis
and both COX-2 and 5-LO inhibitors are being investigated
as potential anticancer drugs. This review article will update
the progress achieved in the knowledge of COX-2 and 5-LO and
discuss the emerging approaches for the pharmacological modulation
of these pathways.
[Back to top]
Eicosanoids in Inflammation: Biosynthesis, Pharmacology,
and Therapeutic Frontiers
Subhash P. Khanapure, David S. Garvey, David R. Janero
and L. Gordon Letts
In mammalian cells, eicosanoid biosynthesis is usually initiated
by the activation of phospholipase A2 and the release of arachidonic
acid (AA) from membrane phospholipids. The AA is subsequently
transformed by cyclooxygenase (COX) and lipoxygenase (LO)
pathways to prostaglandins, thromboxane and leukotrienes collectively
termed eicosanoids. Eicosanoid production is considerably
increased during inflammation. Both COX and LO pathways are
of particular clinical relevance. The COX pathway is the major
target for non-steroidal anti-inflammatory drugs (NSAIDs),
the most popular medications used to treat pain, fever and
inflammation. Although their anti-inflammatory effects are
well known, their long-term use is associated with gastrointestinal
(GI) complications such as ulceration. In 1991, it was discovered
that COX exists in two distinct isozymes, COX-1 and COX-2,
of which COX-2 is primarily expressed at sites of inflammation
and produces pro-inflammatory eicosanoids. For this reason,
COX-2 selective inhibitors (COXIBs) have been developed recently
as anti-inflammatory agents to minimize the risk of GI toxicity.
Recently, some COX-2 selective inhibitors have shown adverse
cardiovascular side effects, resulting in the withdrawal of
rofecoxib and valdecoxib from the market. Selective inhibition
of COX-2 without reducing COX-1-mediated thromboxane production
could alter the balance between prostacyclin and thromboxane
and promote a prothrombotic state, thereby explaining the
observed COX-2 cardiovascular risk. In this review, we describe
mechanisms for the production of pro-inflammatory eicosanoid
mediators contributing to inflammation and summarize promising
options for the prevention of inflammatory mediator formation
and the therapeutic inhibition of pain and inflammation.
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