Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 1, Issue 2, 2007

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..

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.

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.

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.

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.

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.

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.

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.

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 intracardiac adipose tissues as new diagnostic markers and therapeutic targets in obesity management and treatment along with related patents.

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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