| Recent
Patents on Endocrine, Metabolic & Immune Drug Discovery
ISSN: 1872-2148
Recent Patents on Endocrine,
Metabolic & Immune Drug Discovery
Volume 1, Number 2, June 2007
Contents
Hydroxysteroid Dehydrogenase (17β-HSD3,
17β-HSD5,
and 3α-HSD3)
Inhibitors: Extragonadal Regulation of Intracellular Sex Steroid
Hormone Levels Pp.103-118
Michael L. Mohler, Ramesh Narayanan, Yali He, Duane D. Miller
and James T. Dalton
[Abstract]
A Critical View of Molecularly Target Therapy
for Digestive Endocrine Tumours Pp. 119-126
Gabriele Capurso, Stefano Festa, Francesco Panzuto and
Gianfranco Delle Fave
[Abstract]
Which Dose of Folic Acid Should Pregnant Diabetic
Women Receive? Pp. 127-131
Ismael Capel and Rosa Corcoy
[Abstract]
Neural Pathways and Neuropeptides Mediate the Therapeutic
Actions of DPP IV Inhibitors in Type-2 Diabetes Pp.
132-135
Adnan Erol
[Abstract]
The Pineal Gland and Beneficial Effects of Melatonin
Pp. 136-141
Charanjit Kaur and Eng-Ang Ling
[Abstract]
Melatonin and Melatoninergic Drugs as Therapeutic
Agents: Ramelteon and Agomelatine, the Two Most Promising
Melatonin Receptor Agonists Pp. 142-151
Emilio J. Sanchez-Barcelo, Carlos M. Martinez-Campa, Maria
D. Mediavilla, Alicia Gonzalez, Carolina Alonso-Gonzalez and
Samuel Cos
[Abstract]
Targeting Gender Difference in the Introduction of
New Drugs for Diabetes Mellitus and Metabolic Disorders
Pp. 152-156
Flavia Franconi and Giuseppe Seghieri
[Abstract]
Therapeutic Utilisations of Oxytocin and Vasopressin
in Mood Disorders Pp. 157-161
Gabrielle Scantamburlo, William Pitchot, Emmanuel Pinto,
Marc Ansseau and Jean-Jacques Legros
[Abstract]
Cardiac Fat as New Diagnostic Tool and Potential Therapeutic
Target for Obesity Management and Treatment Pp. 162-165
Navneet Singh and Gianluca Iacobellis
[Abstract]
Hepatic Nuclear Factor-4, a Key Transcription Factor
at the Crossroads Between Architecture and Function of Epithelia
Pp. 166-175
Agnès Ribeiro, Amena Archer, Johanne Le Beyec,
Anne-Laure Cattin, Susan Saint-Just, Martine Pinçon-Raymond,
Jean Chambaz, Michel Lacasa and Philippe Cardot
[Abstract]
Patent Selections Pp. 176-181
Abstracts
[Back to top]
Hydroxysteroid Dehydrogenase (17β-HSD3,
17β-HSD5,
and 3α-HSD3)
Inhibitors: Extragonadal Regulation of Intracellular Sex Steroid
Hormone Levels
Michael L. Mohler, Ramesh Narayanan, Yali He, Duane D. Miller
and James T. Dalton
Sex hormone signaling regulates the growth, differentiation
and development of many tissues. The intracellular concentrations
of sex hormones are regulated by several enzymes, including
the 17β-hydroxysteroid
dehydrogenases (17β-HSDs)
and 3α-hydroxysteroid
dehydrogenases (3α-HSDs).
Most notably, these enzymes are involved in the oxidation
and reduction of ketone and β-hydroxyl
groups at the C17 position of androgens and estrogens. Fourteen
mammalian 17β-HSDs
have been identified to date; and are grouped into oxidative
enzymes (17β-HSD
types 2, 4, 6, 8, 9, 10, 11 and 14) that catalyze the NAD+-dependent
inactivation of sex hormones and reductive enzymes (17β-HSD
types 1, 3, 5 and 7) that catalyze the formation of more potent
steroid receptor ligands. The proliferative effects of androgens
and estrogens in target tissues and over-expression of 17β-HSDs
in cancer have led to intense drug discovery efforts to identify
and develop 17β-HSD
inhibitors that can be used for the treatment of breast, prostate
and endometrial cancers, neurological disorders, endometriosis,
acne, hirsutism and other hormone dependent and independent
diseases. Potent and selective inhibitors of intracellular
androgen biosynthesis have been reported and, recent proof-of-concept
data suggests that these agents have utility in the treatment
of androgen-dependent diseases. This review summarizes recent
patents and scientific literature regarding steroidal and
nonsteroidal 17β-HSD3,
17β-HSD5,
and 3α-HSD3
inhibitors and their promise for treatment of androgen-dependent
diseases.
[Back to top]
A Critical View of Molecularly Target Therapy
for Digestive Endocrine Tumours
Gabriele Capurso, Stefano Festa, Francesco Panzuto and
Gianfranco Delle Fave
Enteropancreatic endocrine tumours (EP ETs) are relatively
rare neoplasms constituting a heterogeneous nosological category.
Most EP ETs present with metastatic disease, are well-differentiated
and have a relatively slow growth-rate, with high percentage
of stable disease and relative long survival. In those patients
with progressive disease biotherapy and chemotherapy have
relatively low response rates. In this context, novel therapies
are needed, especially for the treatment of progressive, metastatic
disease which represents, in this field, the main therapeutic
challenge. EP ETs seem an appropriate model for targeting
angiogenesis, with solid data from animal and in vitro
models. Effects of angiogenesis inhibitors, such as bevacizumab,
sunitinib, thalidomide and endostatin seem promising especially
in patients with pancreatic tumours. Targeting other tyrosine
kinases such as EGFR (with gefitinib) or c-KIT (imatinib)
has also been tested, with various degree of response. The
mTOR pathway also looks as an interesting pathway to be targeted,
with interesting data in some clinical trials. The main limits
of the available data are represented by the high heterogeneity
of patients and of inclusion criteria. Moreover, few studies
included patients with documented progressive disease before
treatment, thus making difficult to understand the real efficacy
of treatment on spontaneous tumour growth. Future studies
should evaluate combination therapies in more homogeneous
populations of patients, and include clear definition of the
individual progression rate before and after the study entry.
An informative review of novel patents and therapeutic targets
of enteropancreatic endocrine tumours are also discussed.
[Back to top]
Which Dose of Folic Acid Should Pregnant Diabetic
Women Receive?
Ismael Capel and Rosa Corcoy
It is well established that folate requirements increase during
pregnancy and that supplementing 0.4 mg folic acid/day to
the general pregnant population is beneficial in terms of
reducing the risk of neural tube defects. It is also well
established that offspring of women with pregestational diabetes
mellitus have an increased risk of congenital anomalies. In
animal models, both in vivo and in vitro,
folic acid supplementation reduces glucose-induced congenital
anomalies. In recent years, several academic societies have
included diabetic women in the high-risk category for neural
tube defects, so that the supplementation applying for them
would be 4-5 mg/day, the dose recommended for secondary prevention
in women with a former fetus affected with a neural tube defect.
The protection afforded by folic acid supplementation in diabetic
pregnant women is not clear: multivitamin supplementation
has been reported to reduce the risk of congenital anomalies
but the composition of the supplements was unknown and the
benefit probably included that of overall prepregnancy care.
In addition, in real life, most diabetic women even when planning
pregnancy do not take folic acid supplements. To complicate
things further, folic acid supplementation has potential deleterious
effects, with promotion of neoplasia being among them. Folic
acid tolerable upper intake level is set at 1 mg/day, so that
the aforementioned recommendations should be considered in
the pharmacological range.
After reviewing these issues, we conclude that big efforts
should be made to ensure that diabetic women receive periconceptionally
a folic acid supplementation of 0.4 mg/day, as one of the
interventions of comprehensive prepregnancy care. Until a
favourable risk-benefit ratio is documented, we propose that
higher doses are restricted to women not achieving adequate
blood glucose regulation, and that long periods of supplementation
are avoided.
In recent years there are multiple patents including methods
of detection of abnormalities in folate metabolism and trying
to improve the supplementation of this micronutrient. Only
one of them would be specific for diabetes.
[Back to top]
Neural Pathways and Neuropeptides Mediate the Therapeutic
Actions of DPP IV Inhibitors in Type-2 Diabetes
Adnan Erol
In response to nutrient intake, glucagon-like peptide-1 (GLP-1),
which is considered as an incretin, is secreted from endocrine
cells in gastrointestinal mucosa. With respect to the incretin
effect function of GLP-1, which is reduced significantly in
type 2 diabetes mellitus, how does such a minor amount of
secreted peptide augment insulin secretion by hormonally transduced
signals from the gut even at stabilized endogenous physiolgical
concentrations of GLP-1 by DPP-IV inhibitors? It is necessary
to get a satisfactory mechanistic explanation to positive
preliminary clinical studies done with dipeptidyl peptidase-IV
(DPP-IV) inhibitors in type-2 diabetics. The regulation of
neurally mediated insulin secretion is still neglected concept.
GLP-1 and particularly glucose-dependent insulinotropic polypeptide
(GIP) are exerted not only through a direct action on the
beta cells but may be dependent on indirectly mediated sensory
afferent nerves. Pluripotent glycoprotein enzyme DPP-IV is
a ubiquitously distributed, and inactivates a number of biologically
active peptides such as GIP, pituitary adenylate cyclase-activating
polypeptide (PACAP), gastrin-releasing peptide (GRP), and
glucagon itself, which all have efficient insulinotropic potential.
In addition, it has been shown that DPP-IV inhibitors work
in the central nervous system regulating the function of neuropeptides.
A novel proposal for the mechanism of action of DPP-IV inhibitors
and related patents will be discussed in the paper.
[Back to top]
The Pineal Gland and Beneficial Effects of Melatonin
Charanjit Kaur and Eng-Ang Ling
The pineal gland, a circumventricular organ, is involved in
synchronizing the chronobiology of organisms through synthesis
of melatonin. It is composed of various cell types such as
pinealocytes, macrophages/microglia and astrocytes. The pinealocytes
synthesize and secrete melatonin, the secretion being regulated
by the environmental light/dark cycle via the suprachiasmatic
nucleus. Melatonin has antioxidant, oncostatic, neuroprotective
and immunoregulatory properties, some of which have been reported
by recent patents. Its production is known to decline in old
age and is also known to be affected by certain factors such
as hypoxia-ischemia. Microglia/macrophages have a parenchymal
or perivascular distribution and they may serve as a putative
barrier protecting the pineal gland against entry of serum
derived noxious substances. Besides their supportive role,
the astrocytes in the pineal gland may release growth factors
such as vascular endothelial growth factor under hypoxic conditions
resulting in increased permeability of blood vessels. Our
recent studies have explored the therapeutic potential of
melatonin in ameliorating hypoxic damage in the brain including
the pineal gland.
[Back to top]
Melatonin and Melatoninergic Drugs as Therapeutic
Agents: Ramelteon and Agomelatine, the Two Most Promising
Melatonin Receptor Agonists
Emilio J. Sanchez-Barcelo, Carlos M. Martinez-Campa, Maria
D. Mediavilla, Alicia Gonzalez, Carolina Alonso-Gonzalez and
Samuel Cos
Melatonin is a pineal hormone which basically acts through
membrane receptors, but also as a free radical scavenger (requiring
no receptors), and by binding to intracellular sites (calmodulin
and nuclear receptors). Membrane receptors (MT1,
MT2) are associated to G-proteins
linked to inhibition of adenylyl cyclase and decrease of cAMP,
and are expressed by almost all structures of the CNS (especially
hypothalamic suprachiasmatic nucleus and pars tuberalis of
the pituitary), as well as in peripheral tissues (gastrointestinal
tract, thymus, smooth muscle of blood vessels, adipocytes,
lymphocytes, etc). Among the actions attributed to melatonin
are those of antioxidant, controller of circadian rhythms
(especially sleep-wake and core body temperature), immunomodulation,
antidepressant, etc. This wide spectrum of actions suggests
many possible therapeutic applications for melatonin. However,
its use as a drug presents some limitations (to optimise pharmacological
responses of each subtype or receptors, its rapid metabolic
inactivation, etc.) that have caused many laboratories to
develop analogues without the above mentioned problems. Two
are the patented melatoninergic drugs with more interesting
properties: one is ramelteon (US6034239; Rozerem™),
approved by the FDA for the long-term treatment of sleep disturbances
characterized by difficulty with sleep onset; the second,
agomelatine (US5318994; Valdoxan™), which is completing
the phase III trial, was designed for the treatment of symptoms
of major depressive disorders, particularly anxiety, sleep
troubles and circadian disturbances.
[Back to top]
Targeting Gender Difference in the Introduction of
New Drugs for Diabetes Mellitus and Metabolic Disorders
Flavia Franconi and Giuseppe Seghieri
This review summarizes the important issue of gender difference
in drug response as regards the therapeutic aspect of drugs
utilized for diabetes mellitus and related disorders. Although,
gender differences have been individuated both in experimental
and clinical setting their role in clinical practice is not
yet completely investigated.
Indeed, they are involved in pharmacodinamyc and pharmacokinetics
of antidiabetic drugs but the lack of a gender analysis and
the reduced enrollement of women in clinical studies contributes
widely to this uncertainty. Since sex is a fundamental biological
variable that cannot be discounted, gender differences in
pharmacology has to be considered in order to improve drug
safety efficacy and to optimize medical therapy both in diabetic
men and women also considering the higher incidence, the worst
outcome and the higher mortality for cardiovascular diseases
of diabetic women in comparison with diabetic men.
New drugs, as well as new patents which are considered in
this review, need to take into account these recommendations.
[Back to top]
Therapeutic Utilisations of Oxytocin and Vasopressin
in Mood Disorders
Gabrielle Scantamburlo, William Pitchot, Emmanuel Pinto,
Marc Ansseau and Jean-Jacques Legros
Vasopressin (AVP) and oxytocin (OT) were the first biologically
active peptides to be synthesized. They are two chemically
very similar neurohypophyseal neuropeptides which could be
involved in mood disorders. Neuropeptides, short-chain amino-acid
neurotransmitters and neuromodulators, are attractive therapeutic
targets for mood disorders. AVP seems to play an important
role in the pathophysiology of major depression. There are
both clinical and laboratory evidences suggest a role for
OT as an endogenous antidepressant/anxiolytic hormone. OT
release is also an important aspect of pharmacological action
of SSRIs. In addition to AVP and OT, their receptors are growing
off interest for psychiatric research. Vasopressin receptor
antagonist might represent potential agents for the treatment
of depression. A selective, nonpeptide AVP V1b receptor antagonist,
SSR149415, has been characterized and is endowed with anxiolytic-
and antidepressant-like properties. For the treatment of depression,
Vasopressin antagonist and the related patents are also discussed
in this article.
[Back to top]
Cardiac Fat as New Diagnostic Tool and Potential Therapeutic
Target for Obesity Management and Treatment
Navneet Singh and Gianluca Iacobellis
Targeting adipose tissue via pharmaceutical intervention or
lifestyle interventions is a concept of great interest and
novelty. The importance of proximity of adipose tissue to
the organs is also intriguing. In fact, a body of evidence
shows that regional fat distribution, particularly the visceral
fat compartment, plays a role in the development of an unfavourable
cardio-metabolic profile, rather than overall adiposity. Intuitively,
visceral adipose tissue, now clinically measurable by simple,
accurate and reliable diagnostic tools, is the most desirable
therapeutic target. Changes in regional fat distribution can
be used to estimate drugs effectiveness and their mechanism
of action. Among visceral adipose tissues, a body of evidence
suggests that cardiac adiposity may play an important role
in the development of an unfavorable cardiovascular risk profile.
Epicardial and intra-cardiac fat are new and promising markers
of cardiac and visceral adiposity and increased cardiovascular
risk. This article briefly deals with the perspective and
potential of epicardial and intra-cardiac adipose tissues
as new diagnostic markers and therapeutic targets in obesity
management and treatment along with related patents.
[Back to top]
Hepatic Nuclear Factor-4, a Key Transcription Factor
at the Crossroads Between Architecture and Function of Epithelia
Agnès Ribeiro, Amena Archer, Johanne Le Beyec,
Anne-Laure Cattin, Susan Saint-Just, Martine Pinçon-Raymond,
Jean Chambaz, Michel Lacasa and Philippe Cardot
Hepatic nuclear factor-4 (HNF-4) is a transcription
factor and a member of the large family of nuclear receptors.
It was first cloned from liver but is expressed also in kidney,
pancreas and intestine. Three genes encoding three isoforms
have been identified, HNF-4α
and γ,
in mammals, drosophila and xenopus and HNF-4β,
exclusively in xenopus. HNF-4α
is the best studied isoform, especially in liver. Such studies
put HNF-4α
at the crossroads between architecture and function of epithelia,
as it induces expression of cell/cell junction proteins while
it also controls glucido-lipidic metabolism and drug metabolizing
enzyme genes. Furthermore, mutations in the HNF-4α
gene lead to a metabolic disease in humans, Maturity Onset
Diabetes of the Young-1 (MODY-1). The existence of a “true
ligand” is not clearly established but a “structural”
fatty acid is present in the ligand binding pocket of HNF-4α
and γ.
Consequently, activity of HNF-4 can be modulated by the interaction
with co-regulators or by post-translational modifications.
Then, HNF-4 is a potential direct or indirect target for pharmacologic
drugs, with a special interest for the intestinal epithelium
which is the primary site of metabolic control, due to its
roles in nutrient absorption and in sensing energy. The patents
related to the HNF-4α
gene are also discussed in this article.
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