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Recent Patents
on Cardiovascular Drug Discovery
ISSN: 1574-8901
Recent Patents on Cardiovascular
Drug Discovery
Volume 1, Number 1, January 2006
Contents
Novel Molecular Targets in the Treatment of Cardiac Hypertrophy
Pp.1-20
Mark Luedde, Hugo A. Katus & Norbert Frey
[Abstract] [Full
Text Article]
Non-Steroidal LXR Agonists; An Emerging Therapeutic Strategy
for the Treatment of Atherosclerosis Pp.21-46
David J. Bennett, Andrew J. Cooke & Andrew S.
Edwards
[Abstract] [Full
Text Article]
Methods for Identifying Cardiovascular Agents: A Review Pp.47-56
David Anthony Tulis
[Abstract] [Full
Text Article]
Recently Patented Applications of Homologous Cellular and
Extracellular Agents as Therapeutics or Targets for the Prevention
of Restenosis Post-Angioplasty Pp.57-66
Rainer Klocke, Lekbira Hasib & Sigrid Nikol
[Abstract] [Full
Text Article]
Soluble Epoxide Hydrolase: A Novel Target for the Treatment
of Hypertension Pp.67-72
Xiang Fang
[Abstract] [Full
Text Article]
Combination of a Sterol Absorption Inhibitor and Cardiovascular Agents for the Treatment of Dyslipidemia
Pp.73-78
Christina Chrysohoou & Steven Singh
[Abstract] [Full
Text Article]
Telmisartan, its Potential Therapeutic Implications in Cardiometabolic
Disorders Pp.79-83
Sho-ichi Yamagishi & Kazuo Nakamura
[Abstract] [Full
Text Article]
Edaravone (3-Methyl-1-Phenyl-2-Pyrazolin-5-one), A Novel Free
Radical Scavenger, for Treatment of Cardiovascular Diseases
Pp.85-93
Yukihito Higashi, Daisuke Jitsuiki, Kazuaki Chayama
& Masao Yoshizumi
[Abstract] [Full
Text Article]
The Vascular Endothelin System in Hypertension - Recent Patents
and Discoveries Pp.95-108
Meri M. Hynynen & Raouf A. Khalil
[Abstract] [Full
Text Article]
New Approaches to Atherosclerotic Cardiovascular Disease.
The Potentialities of Torcetrapib Pp.109-114
Jose Luis Pérez-Castrillon & Antonio Dueñas-
Laita
[Abstract] [Full
Text Article]
Patent Annotations
Pp.115-117
Patent Selections
Pp.119-128
Abstracts
[Back to top]
Novel Molecular Targets in the Treatment of Cardiac Hypertrophy
Mark Luedde, Hugo A. Katus & Norbert Frey
[Full
Text Article]
Left ventricular hypertrophy represents the heart’s
response to increased biomechanical stress such as arterial
hypertension or valvular heart disease. Cardiac hypertrophy
has traditionally been considered a compensatory mechanism
required to normalize wall tension and to maintain cardiac
output. However, recent clinical studies as well as several
animal models have shown that sustained cardiac hypertrophy
is rather a maladaptive process, ultimately leading to heart
failure and sudden death independent of the underlying cause
of hypertrophy.
Throughout the past decade, much effort has thus been spent
on deciphering the molecular signaling pathways mediating
cardiac growth. Identification of novel molecules regulating
cardiac hypertrophy could offer the basis for a new generation
of cardiovascular drugs. In this review we focus on recent
insights into hypertrophic signaling and consider current
and emerging approaches to inhibit hypertrophy with the ultimate
goal to prevent or delay the onset of heart failure and sudden
death in patients.
[Back to top]
Non-Steroidal LXR Agonists; An Emerging Therapeutic Strategy
for the Treatment of Atherosclerosis
David J. Bennett, Andrew J. Cooke & Andrew S.
Edwards
[Full Text Article]
The Liver X Receptor (LXR) α
and ß isoforms are members of the type II nuclear receptor
family which function as obligate heterodimers with the Retinoid
X Receptor (RXR). Upon agonist binding, the DNA Binding Domain
(DBD) of LXR interacts with LXR response elements on target
genes to initiate transcription. A number of genes have been
shown to be modulated by LXR function, including the ATP-binding
cassette transporter A1 (ABCA1). ABCA1 is involved in the
process of reverse cholesterol transport (RCT) from macrophages
in atherosclerotic plaques to high-density lipoproteins (HDL)
in the plasma. Both homozygous and heterozygous mutations
in ABCA1 result in conditions characterised by decreased levels
of HDL and an earlier onset of atherosclerosis. A number of
other genes are upregulated by LXR activation which would
be expected to have either pro- or anti-atherogenic effects.
One such target gene is sterol regulatory element binding
protein-1c (SREBP-1c), which is involved in the process of
lipogenesis leading to increased levels of triglycerides which
are pro-atherogenic. The complexity of LXR responses, however,
makes it difficult to extrapolate the ‘positive’
or ‘negative’ effects of each target gene in isolation
to a conclusion as to the outcome in humans when all target
genes are being modulated in concert. This review will cover
the structural features and associated biological data of
non-steroidal LXR modulators claimed for the treatment of
cardiovascular disease, as well as highlighting preferred
compounds where this information can be discerned. In addition
to this patent information a précis of literature data
relevant to the utility of specific compounds in the treatment
of cardiovascular disease will be given where available.
[Back to top]
Methods for Identifying Cardiovascular Agents: A Review
David Anthony Tulis
[Full Text Article]
Basic and clinical investigation into many of the diverse
aspects of cardiovascular drug discovery employs varied approaches
aimed at determining physiologic and pathophysiologic efficacy
of candidate agents for therapeutic utility with the ultimate
hope of identifying those agents capable of exerting salutary
influence upon cardiac and vascular tissues. Promising compounds
may then be used for prophylactic cardiovascular protection
and for the treatment of various disorders including hypertension,
cardiomyopathy, occlusive vascular disease, and heart failure.
The invention disclosed in Methods for identifying cardiovascular
agents [1] provides screening methods which can be used
to identify certain suspected cardiovascular agents that inhibit
vascular smooth muscle cell (VSMC) activation and/or proliferation,
functional adaptations inherent in the responses to disease
or injury, or those that enhance vascular endothelial cell
(VEC) activation and/or proliferation, processes thought to
provide protection to jeopardized blood vessels. Additionally,
these screening assays include agents that activate estrogen
responsive genes in vascular cells, considering that estrogen
signaling is generally suggested to serve pivotal functions
in preventing many of the pathologic mechanisms contributing
to occlusive vascular complications. The findings of this
primary patent are directly relevant for discoveries in related
inventions that disclose various provisions for cardiovascular
drug discovery. This review will provide detailed synopses
of these function-based screening methods capable of identifying
cardiovascular protective agents for use in basic science
research and clinical drug discovery.
[Back to top]
Recently Patented Applications of Homologous Cellular and
Extracellular Agents as Therapeutics or Targets for the Prevention
of Restenosis Post-Angioplasty
Rainer Klocke, Lekbira Hasib & Sigrid Nikol
[Full Text Article]
Currently available drug-eluting stents have been shown to
reduce the prevalence of in-stent restenosis. However, their
use is limited by their enormous cost and unwanted side effects
associated with both drugs, sirolimus and paclitaxel, presently
used to coat most of the stents clinically avilable. Due to
their lack of selectivity with respect to targeted cell types
these drugs do not only inhibit vascular smooth muscle cell
proliferation underlying neointima formation, they also compromise
endothelial repair increasing the risk for subacute thrombosis
following implantation of drug-eluting stents. Accordingly,
there is need for new cost-effective agents capable to inhibit
restenosis without clinically relevant, unwanted side effects.
In the present paper, a selection of the most important patent
applications published within the last 3 years and claiming
the use of homologous cellular and extracellular agents as
therapeutics or targets to prevent restenosis are reviewed.
Such agents include c-Jun, the focal adhesion kinase (FAK)
and its inhibitor FAK-related non-kinase (FRNK), estrogen
receptors, variants of vascular endothelial growth factor
(VEGF) and fibroblast growth factor-2 (FGF-2) as well as some
so far poorly characterized factors supposedly involved in
the control of cell proliferation, inflammation and apoptosis.
Such agents promise to be cost-effective and, in some cases,
potentially devoid of unwanted side effects. Clinical long-term
studies have yet to support such notions.
[Back to top]
Soluble Epoxide Hydrolase: A Novel Target for the Treatment
of Hypertension
Xiang Fang
[Full Text Article]
Epoxide hydrolases are a group of enzymes that convert the
epoxide group of chemical compounds to corresponding diols
by the addition of water. Soluble epoxide hydrolase (sEH,
formerly referred to as cytosolic epoxide hydrolase), which
is widely distributed in mammalian tissues, is the primary
enzyme responsible for the conversion of epoxyeicosatrienoic
acids (EETs), the bioactive lipid mediators formed from arachidonic
acid by cytochrome P450 epoxygenase, to their corresponding
diols. EETs, but not their diols, are endogenous anti-hypertensive
eicosanoids. Disruption of the sEH gene in male mice decreases
blood pressure, and inhibition of sEH decreases blood pressure
in several experimental hypertensive models. Potent selective
sEH inhibitors have been developed, and these sEH inhibitors
have potential to become a novel class of anti-hypertensive
drug.
[Back to top]
Combination of a Sterol Absorption Inhibitor and Cardiovascular Agents for the Treatment of Dyslipidemia
Christina Chrysohoou & Steven Singh
[Full Text Article]
Although statins are effective in reducing cardiovascular
risk, combination therapy may be required to meet recommended
target LDL-C levels. However, the utility of current combination
therapies with niacin or bile acid sequestrants is limited
by side effects and compliance. Ezetimibe, as a selective
cholesterol absorption inhibitor, represent a new class of
pharmaceutical agents. The combination of ezetimibe with statins
has shown a 16-21% increase in the percentage of patients
achieving their ATP III LDL-C goal. Randomized, double-blind
studies have shown that coadministration of ezetimibe with
simvastatin is well tolerated, causing dose-dependent reduction
in LDL-C and total cholesterol levels, with no apparent effect
on high-density lipoprotein cholesterol or triglycerides.
Even in diabetes mellitus type 2 patients; the addition of
ezetimibe 10 mg to simvastatin 20 mg is more efficacious than
doubling the dose of simvastatin in lowering lipid parameters.
Similarly the coadministration of ezetimibe and rosuvastatin,
has shown a mean incremental reduction in LDL-C of –16%,
compared with rosuvastatin alone, while there was no apparent
effect on HDL-C or triglycerides. Ezetimibe and fenofibrate
co-administration has shown also improvement in the lipid/lipoprotein
profile. The combination therapy with ezetimibe and statin
or fibrate may be an effective therapeutic option for patients
with dyslipidemia.
[Back to top]
Telmisartan, its Potential Therapeutic Implications in
Cardiometabolic Disorders
Sho-ichi Yamagishi & Kazuo Nakamura
[Full Text Article]
There is a growing body of evidence that the renin-angiotensin
system (RAS) plays a pivotal role in the pathogenesis of cardiovascular
diseases. Indeed, large clinical trials have demonstrated
substantial benefit of the blockade of this system for cardiovascular-organ
protection. Although several types of angiotensin II type
1 (AT1) receptor blockers (ARBs) are commercially available
for the treatment of patients with hypertension, we have recently
found that telmisartan (Micardis) could have the strongest
binding affinity to AT1 receptor. Telmisartan will be a promising
cardiometabolic sartan due to its unique peroxisome proliferator-activated
receptor-γ
(PPAR-γ)-inducing
properties as well. In this review, we focused on telmisartan,
and discussed its potential therapeutic implications in cardiometabolic
disorders.
[Back to top]
Edaravone (3-Methyl-1-Phenyl-2-Pyrazolin-5-one), A Novel
Free Radical Scavenger, for Treatment of Cardiovascular Diseases
Yukihito Higashi, Daisuke Jitsuiki, Kazuaki Chayama
& Masao Yoshizumi
[Full Text Article]
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a strong
novel free radical scavenger, is used for treatment of patients
with acute brain infarction. Edaravone has preventive effects
on myocardial injury following ischemia and reperfusion in
patients with acute myocardial infarction. Antioxidant actions
of edaravone include enhancement of prostacyclin production,
inhibition of lipoxygenase metabolism of arachidonic acid
by trapping hydroxyl radicals, inhibition of alloxan-induced
lipid peroxidation, and quenching of active oxygen, leading
to protection of various cells, such as endothelial cells,
against damage by reactive oxygen species (ROS). Recently,
we have shown that edaravone improves endothelial function
through a decrease in ROS in smokers. From a clinical perspective,
it is important to select an appropriate drug that is effective
in improving endothelial function in patients with cardiovascular
diseases. The novel free radical scavenger edaravone may represent
a new therapeutic intervention for endothelial dysfunction
in the setting of atherosclerosis, chronic heart failure,
diabetes mellitus, or hypertension. This review focuses on
clinical findings and on putative mechanisms underlying the
beneficial effects of the antioxidative agent edaravone on
the artherosclerotic process in patients with cardiovascular
diseases.
[Back to top]
The Vascular Endothelin System in Hypertension –
Recent Patents and Discoveries
Meri M. Hynynen & Raouf A. Khalil
[Full Text Article]
The discovery of endothelin two decades ago has now evolved
into an intricate vascular endothelin (ET) system. Several
ET isoforms, receptors, signaling pathways, agonists, antagonists,
and clinical applications have been identified and documented
in first-rate patents. The role of ET as one of the most potent
endothelium-derived vasoconstricting factors is now complemented
by a newly discovered role in vascular relaxation. ET synthesis
is initiated by the transcription of ET genes in endothelial
cells and the generation of the gene products preproET and
big ET, which are further cleaved by specific ET converting
enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind
with different affinities to ETA and ETB2 receptors in vascular
smooth muscle, and stimulate [Ca2+]i, protein kinase C, mitogen-activated
protein kinase and other signaling mechanisms of smooth muscle
contraction, growth and proliferation. ET also binds to endothelial
ETB1 receptors, which mediate the release of vasodilator substances
such as nitric oxide, prostacyclin and endothelium-derived
hyperpolarizing factor. Endothelial ETB1 receptors may also
function in ET re-uptake and clearance. Although, the effects
of ET on vascular function and growth are well-recognized,
the role of ET and its receptors in the regulation of blood
pressure and in the pathogenesis of hypertension is not clearly
established. Salt-dependent hypertension in experimental animals
and some forms of moderate to severe hypertension in human
may show elevated levels of plasma or vascular ET; however,
other forms of hypertension show normal ET levels. The currently
available ET receptor antagonists reduce blood pressure in
some forms of experimental hypertension. Careful examination
of recent patents may identify more effective and specific
modulators of the vascular ET system for clinical use in human
hypertension.
[Back to top]
New Approaches to Atherosclerotic Cardiovascular Disease.
The Potentialities of Torcetrapib
Jose Luis Pérez-Castrillon & Antonio Dueñas-
Laita
[Full Text Article]
Atherosclerosis is the leading cause of death and disability
in the developed world. Although the low-density lipoprotein
(LDL) cholesterol lowering drugs reduce the mortality and
morbidity associated with coronary artery disease, considerable
mortality and morbidity remains. Reverse cholesterol transport
mediated by high-density lipoproteins (HDL) may provide an
independent pathway for lipid removal from atheroma. The current
NCEP ATPIII include HDL-cholesterol =1.6 mmol/l as a negative
risk factor. Torcetrapib is an inhibitor of cholesteryl ester-transfer
protein (CETP) that increases high-density lipoprotein (HDL)
cholesterol levels. The drug increases HDL-cholesterol and
apolipoprotein A-I levels and decreases LDL-cholesterol and
apolipoprotein B levels. The effect is showed in monotherapy
and when administered in combination with statins. In addition,
torcetrapib did not significantly change the serum levels
of cholesterol and triglycerides. The raising HDL-cholesterol
with torcetrapib could be a new approach to atherosclerotic
cardiovascular disease although new trials based on hard clinical
end points are necessary.
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