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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 4, 2006
Contents
Towards Selective Kir6.2/SUR1 Potassium Channel Openers, Medicinal
Chemistry and Therapeutic Perspectives Pp. 361-376
John Bondo Hansen
[Abstract]
Towards Species-specific Antifolates Pp.
377-398
D.C.M. Chan and A.C. Anderson
[Abstract]
Dimeric and Hybrid Anti-Alzheimer Drug Candidates
Pp. 399-422
D. Muñoz-Torrero and P. Camps
[Abstract]
Chemical Toxicity on HeLa Cells Pp. 423-448
Rajeshwar P. Verma and Corwin Hansch
[Abstract]
Modulation of Renal Tubular Cell Survival: Where is
the Evidence? Pp. 449-454
C. Lorz, A. Benito-Martin, P. Justo, A.B. Sanz, M.D. Sanchez-Niño,B.
Santamaria, J. Egido and A. Ortiz
[Abstract]
Fluoroquinolones: An Important Class of Antibiotics
Against Tuberculosis Pp. 455-463
Marcus Vinícius Nora De Souza, Thatyana Rocha Alves
Vasconcelos,Mauro Vieira de Almeida and Sílvia Helena
Cardoso
[Abstract]
A Role for Leptin in the Systemic Inflammatory Response
Syndrome (SIRS) and in Immune Response, an Update
Pp. 465-475
W. Waelput , P. Brouckaert, D. Broekaert and J. Tavernie
[Abstract]
Abstracts
[Back to top]
Towards Selective Kir6.2/SUR1 Potassium
Channel Openers, Medicinal Chemistry and Therapeutic Perspectives
John Bondo Hansen
ATP sensitive potassium (KATP) channels have important
functions in neuroendocrine tissue, in smooth and skeletal
muscle and in the heart. In pancreatic beta cells the KATP
channels, which are formed by 4 ion channels (Kir6.2) and
4 regulatory sulfonylurea receptors (SUR1), control the glucose
stimulated release of insulin. The Kir6.2/SUR1 KATP channels
are also present in the brain and in other neuroendocrine
tissues. Blockers of Kir6.2/SUR1 channels, e.g. glibenclamide
and repaglinide stimulate release of insulin and are used
for treatment of type 2 diabetes. Openers of Kir6.2/SUR1 channels,
e.g. diazoxide, have in contrast only found limited clinical
use in treatment of hypersecretion of insulin associated with
certain tumours (insulinoma) and genetic disorders (persistent
hyperinsulinemia and hypoglycemia of infancy, PHHI). Recent
studies have however, indicated that openers of Kir6.2/SUR1
channels could be useful in treatment of e.g. metabolic disorders
and diseases of the CNS. The clinical use of diazoxide has
been hampered by its lack of potency and selectivity giving
rise to side effects, such as oedema and hirsutism and new
selective openers of Kir6.2/SUR1 channels have been pursued.
This has provided several structurally diverse series, which
include 1,2,4-thiadiazine 1,1-dioxide derivatives, like BPDZ
62, BPDZ 73, NNC 55-0462, NNC 55-0118 and NN414, cyanoguanidines,
nitropyrazoles and 4-sulfamoylphenylbenzamides. NN414 has
been shown to be a potent and Kir6.2/SUR1 selective KATP
channels opener, which inhibits glucose stimulated insulin
release in vitro and in vivo and which has beneficial effects
on glucose homeostasis in preclinical and clinical studies.
[Back to top]
Towards Species-specific Antifolates
D.C.M. Chan and A.C. Anderson
Dihydrofolate reductase (DHFR) plays an essential role in
cellular biochemistry and has been a well-recognized drug
target for over fifty years. Antifolate inhibitors of DHFR,
including clinically used therapeutics such as methotrexate,
trimethoprim, and pyrimethamine have been successful as anticancer,
antibacterial, antifungal and antiparasitic agents. As resistant
strains of these microorganisms evolve and as new disease
threats arise, the need for new antifolates that are potent
and specific for infectious organisms becomes more pressing.
Several new antifolates have been reported over the past decade;
many of these are potent against a particular species of DHFR,
but achieving the goal of potency and selectivity has proven
to be more difficult. This review will describe recent advances
in attaining species selectivity in developing new antifolates.
Specifically, advances in developing inhibitors against Pneumocystis
jirovecii and Plasmodium falciparum, the causative
agents in pneumocystis pneumonia and malaria, respectively,
will be presented
[Back to top]
Dimeric and Hybrid Anti-Alzheimer Drug Candidates
D. Muñoz-Torrero and P. Camps
In the last decade much attention has been paid to the development
of metabolically non-reversible dimeric or hybrid compounds,
which combine two structural units of one or two lead compounds
of interest for the treatment of Alzheimer’s disease.
As a consequence of their capability to simultaneously interact
with two binding sites of the same biological target (the
enzyme acetylcholinesterase in most cases), to expand their
interaction in the main binding site of the target molecule,
or to interact with two different biological targets of interest
in the pathogenesis of the disease, these dimeric or hybrid
compounds exhibit an improved pharmacological profile including
high affinity interactions, additional non conventional actions
or complementary actions, what makes them potential drug candidates
for the treatment of Alzheimer’s disease. Herein, we
review from a structural point of view the main classes of
dimeric or hybrid compounds developed for the treatment of
Alzheimer’s disease, along with the pharmacological
profile of the most active compounds.
[Back to top]
Chemical Toxicity on HeLa Cells
Rajeshwar P. Verma and Corwin Hansch
HeLa cells were named for Henrietta
Lacks, who died in 1952 from an
infection of a special type of cancer. Margaret Gey, her physician,
started working with these cancer cells that are still used
for medical research. In the present review, an attempt has
been made to collect the data for the effects of different
chemicals on HeLa cells and to discuss them by the formulation
of a total number of 22 QSAR.
[Back to top]
Modulation of Renal Tubular Cell Survival: Where is
the Evidence?
C. Lorz, A. Benito-Martin, P. Justo, A.B. Sanz, M.D. Sanchez-Niño,B.
Santamaria, J. Egido and A. Ortiz
Tubular cell loss is prominent both in acute and chronic
renal failure. Apoptosis and its regulatory mechanisms contribute
to cell number regulation in the kidney. The potential role
of apoptosis ranges from induction and progression to repair
of renal injury. However, therapeutic interest has focused
in preventing the apoptotic loss of tubular cells that leads
to acute and chronic renal failure. Death ligands and receptors,
such as tumor necrosis factor and Fas ligand, proapoptotic
and antiapoptotic Bcl2 family members and caspases have all
been shown to participate in apoptosis regulation in the course
of renal cell injury. Nevertheless, the precise role of these
proteins is unclear, and the participation of most known apoptosis
regulatory proteins has not been studied. We now review the
role of apoptosis in renal injury, the potential molecular
targets of therapeutic intervention, the therapeutic weapons
to modulate the activity of these targets and the few examples
of therapeutic intervention on apoptosis, with emphasis in
acute renal failure.
[Back to top]
Fluoroquinolones: An Important Class of Antibiotics
Against Tuberculosis
Marcus Vinícius Nora De Souza, Thatyana Rocha Alves
Vasconcelos,Mauro Vieira de Almeida and Sílvia Helena
Cardoso
Tuberculosis (TB) is a global health problem due to the lack
of new drugs in the market and also due to the advent of multidrug
resistant strains (MDR). This disease affects around 8 million
people and kills almost 3 million people each year and it
is estimated that there are 1 billion infected with TB worldwide.
Due to this problem fluoroquinolones have attracted much attention
as the new class of anti TB drugs due to their fewer toxic
side effects, improved pharmacokinetic properties and extensive
and potent activity against Gram-positive and Gram-negative
bacteria, including resistant strains. In this present review
we report fluoroquinolones as a promising new class of anti
TB.
[Back to top]
A Role for Leptin in the Systemic Inflammatory Response
Syndrome (SIRS) and in Immune Response, an Update
W. Waelput , P. Brouckaert, D. Broekaert and J. Tavernie
Leptin was originally identified as an adipocyte-derived
cytokine with a key role in the regulation of the energy balance.
Subsequent research revealed that leptin’s biological
action is not restricted to its effects on appetite and food
intake, but instead has a much more pleiotropic character.
There is now ample evidence that leptin has important functions
in reproduction, hematopoiesis, HPA-axis endocrinology and
angiogenesis. In this review we have focused on the effects
of leptin in the antigen-specific immunity and in the inflammatory
effector system.
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