Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 5, Issue 3, 2011

Leptin, the protein product of the ob gene, is primarily an adipocyte-secreted hormone, whose functional significance is rapidly expanding. Although early research efforts were focused on defining leptin's role in reversing obesity in rodents, there is now substantial evidence indicating that its influence extends to a number of hypothalamic-pituitaryendocrine axes, including adrenal, gonadal, growth hormone, pancreatic islets, and thyroid. The pleiotropic nature of leptin has been confirmed by demonstration of a role for leptin in hematopoiesis, angiogenesis, immune function, osteogenesis, reproduction, and wound healing. Unfortunately, the results of the majority of clinical trials with recombinant human leptin indicated that its effectiveness in restoring energy balance and correcting obesity-related endocrinopathies in genetically obese rodent models extended only to the management of those rare forms of human obesity caused by mutation in the ob gene. Failure of leptin in the clinic, and withdrawal of fenfluramine, phentermine, and sibutrimine from clinical use in the United States, have stimulated new approaches in the development of anti-obesity and anti-diabetes pharmacophores. These efforts are focused on utilizing leptin-related synthetic peptides as leptin receptor antagonists or leptin-related synthetic peptide analogs or mimetics. This review summarizes patents on leptin-related peptide analogs, antagonists and mimetics.

Incretins, which are insulinotropic gastrointestinal hormones, are produced mainly in K and L cells of the small intestine under the influence of nutritional stimuli. The best known incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones perform several functions: they stimulate insulin secretion in the pancreatic beta cells; they inhibit glucagon release from the alpha cells of the pancreas (GIP not in humans); they slow down gastric emptying and may directly suppress appetite; and, moreover, they indirectly increase peripheral glucose tolerance/insulin sensitivity. The insulinotropic and glucagonostatic effects of GLP-1 are glucose dependent. The incretins also have numerous other properties which are still being discovered and introduced in different branches of medicine. The patents mentioned in this work concern the use of incretins in diabetology, cardiology, gastroenterology and nuclear medicine. The pleiotropic effects of incretins offer therapeutic possibilities in numerous fields of medicine.

Discovery of new cancer drugs is important for the improvement of disease treatment and management. In addition to the clear medical needs there are also economic considerations: Much drug discovery is performed in the private sector. The high cost of some drug treatments, which can run to tens of thousands of US$ per patient for single courses of therapy has led to the perception of high profitability in the industry. But drug discovery and development is a very expensive and lengthy process, with an ongoing trend of fewer drugs brought to market per dollar invested in R&D. Biochemical-based in vitro screens for hosts of targets have produced early stage drug candidates and led to drugs reaching the market, but there remains a great need to evaluate in vivo efficacy, toxicity and potential off-target effects as early as possible in the discovery process. Using whole organisms much earlier in cancer (and other) drug discovery is a potential approach to improve R&D productivity. Here, we provide an overview of recent patenting activity and take a brief look at possible new developments in the field.

Thalidomide has a broad spectrum of anti-cancer activity. Antitumor activity of thalidomide may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-α and T-cell costimulatory and antiangiogenic activities. The therapeutic potential of thalidomide provided motivation to develop more effective derivatives with considerably reduced toxicity. Thalidomide's immunomodulatory (IMiDs) analogs (lenalidomide, CC-5013; CC-4047, ACTIMID) represent a novel class of compounds with numerous effects on the immune system. Some of these analogs are thought to mediate the anticancer and anti-inflammatory effects observed in humans. Thalidomide is currently approved for the treatment of dermal reaction to leprosy and is currently in phase III trials for multiple myeloma (MM). IMiDs inhibit the cytokine's tumor necrosis factor-α (TNF-α), interleukins (IL) 1β, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). The repression of the tumor necrosis factor-a (TNF-a) expression is the crucial factor of many of the anti-inflammatory properties of thalidomide. The mechanisms underlying many of the anti-inflammatory properties of thalidomide, including its ability to co-stimulate T cells, still remain unclear. Some recent patent are also summarized in this review.

The dipeptidyl peptidase-4 (DPP-4) inhibitors linagliptin, sitagliptin, saxagliptin, vildagliptin and alogliptin are being developed and have been approved for the treatment of type-2 diabetes. These agents may be used either as monotherapy for the treatment of type-2 diabetes or in combination with other anti-diabetic drugs. The present review highlights the use of linagliptin and other new (DPP-4) inhibitors in the management of type-2 diabetes. The review also highlights advantages, comparative pharmacokinetic, safety profile and other potential uses including potential newer indications of DPP-4 inhibitors and relevant patents. The other potential uses that are not restricted to diabetes include obesity, cardiovascular disease, neurological disease, hepatobiliary disease, wound healing, and other inflammatory illnesses. Diabetes

The present review summarizes the existing literature data regarding the development of newer categories of antidiabetic agents, their mechanism of action and their clinical importance. In this paper, a review of the recent patents for the treatment of diabetes will be presented. In recent years significant achievements have been done, including the development of SGLT2 inhibitors, glucokinase activators as well as the role of free fatty acids and bile acid metabolism in the treatment of diabetes are reviewed.

17β-Estradiol (E2), via its cognate receptors (ERs), regulates several aspects of human physiology including development, reproduction and tissue homeostasis. Consequently, E2 could also be implicated in the development or progression of several pathologies, including cancer. Two different ER subtypes are present in mammals (ERα and ERβ), which display specific roles in E2-related cancers, different tissue distribution, and multiple action mechanisms (i.e., genomic and extranuclear mechanisms). Here, the complex pattern of the relative contribution of each ER subtype in the E2- dependent cancers has been summarized by taking into consideration the molecular events which occur both in the nucleus and in extranuclear compartments. In the second part of this paper, we reviewed the current literature available on the drug-targeting of the ERs, as well as the recent literature and patents describing new and upcoming molecules. These new molecules will probably greatly improve the repertoire of anti-hormonal therapeutic strategies. However, further new drug design programs, which should include all molecular mechanisms at the basis of ER biology, are needed to expand the anti-ER treatments in new and more efficient therapeutic directions. This review also outlines relevant patents.

Beta adrenergic receptors are very important in respiratory medicine. Traditionally, the stimulation of beta adrenergic receptors by beta2-agonists is commonly used for giving bronchodilation in chronic airflow obstruction However; the wide distribution of these receptors in cells and tissues other than airway smooth muscle suggests that beta agonists should offer other beneficial effects in respiratory disease. Recent studies have shown the importance of these receptors in the modulation of endocrine and immune system that affect respiratory function and may decrease therapy effectiveness in asthma and chronic obstructive pulmonary disease. New patented compound and uses have provided new insights in future therapeutics of respiratory diseases in which genetic, endocrine and immune response should be considered.

Risperidone have been reported to commonly lead to asymptomatic elevation of liver enzymes in adult population, and recently in children and adolescents. Results from controlled clinical trials, reports of spontaneous adverse events, and published studies/ case reports suggest that severe hepatotoxicity may be rare but can occur in the pediatric population. In the following case report, we describe a 5-year-old male patient diagnosed as autism with severe distruptive behavior. Substantial improvement was achieved with risperidone therapy. Increase in liver enzymes at the beginning of the risperidone treatment was successfully managed with multidisciplinary approach as the treatment was initially withdrawn, afterwards restarted and carefully continued. We demonstrated that risperidone may be cautiously rechallenged in selected pediatric patients who showed marked psychiatric improvement with risperidone on the face of liver enzymes elevation. Some important patents on risperidone delivery and their use for the treatment of autism are also outlined.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets & therapeutic agents related to endocrine, metabolic and immune drug discovery.