Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 2, Issue 3, 2008

Mammalian and human cells contain multiple forms of proteasomes different in their structure and functions. 26S-proteasome pool regulates most cellular processes through ATP- and ubiquitin-dependent hydrolysis of proteins participating in these processes. This function is possible due to 19S-subparticle capable to recognize ubiquitinated proteins, unfold and direct them into the proteolytic chamber. 20S-proteasome pool is capable to degrade some damaged and foreign proteins in an ATP- and ubiquitin-independent manner. Among both proteasome pools, the immune proteasomes effectively produce antigen epitopes for MHC class I molecules and play a crucial role in the antitumor immunity. Excluding the immune proteasomes from their cells, numerous tumors avoid the immune system. On the contrary, tumor cells enhance the expression of the housekeeping proteasomes and 19S-subparticle. At this time, bortezomib, a patented proteasome inhibitor, is used as an anticancer therapy. This drug induces the cell cycle arrest and apoptosis of dividing tumor cells. However, bortezomib causes, firstly, deviations in immune functions, secondly, the increase of the housekeeping proteasome expression by a feedback mechanism. Taking into account the recent patents, we consider prospects of the development of new drugs directed to the regulation of the expression of the immune and housekeeping proteasomes and 19S-subparticle in tumor cells.

The clinical efficacy and tolerability of dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes is supported by published clinical trials. Primary literature and review articles were obtained via a Pubmed search (2002-2008) using the search terms diabetes, sitagliptin, vildagliptin and DPP-4 inhibitors. Eleven sitagliptin trials were identified and reviewed along with 14 vildagliptin studies. Clinical data pertinent to this review were also included. Sitagliptin and vildagliptin belong to a new class of therapeutic agents which enhance endogenous levels of active incretin hormones by inhibiting their degradation by the enzyme DPP-4. The agents have been studied as monotherapy; as add-on therapy to metformin, a sulfonylurea, a thiazolidinedione, and insulin; and as initial-combination therapy with a thiazolidinedione. In clinical trials, treatment with DPP-4 inhibitors produced clinically significant reductions in hemoglobin A1c (A1C). In clinical trials, treatment was weight-neutral and had a rate of hypoglycemia similar to that of placebo. DPP-4 inhibitors have proven efficacy in reducing A1C levels as monotherapy or in combination with other commonly prescribed glucose-lowering agents. More recent phase III trials indicate a sustained effect on reducing blood glucose in type 2 diabetes. DPP-4 inhibitor treatment is well tolerated both as monotherapy and in combination with other agents. This review article also discusses some related patents.

In the fields of genomic, proteomic and metabolomic technologies many advances have been made in the past few years for the early diagnosis and monitoring of diseases such as diabetes mellitus. As diabetes is afflicting affluent and developing societies throughout the world and is fuelled by aging demographics and the recent increase of obesity and related insulin resistance, there is a clear need to discover effective agents for diagnosing the disease and controlling glycaemic status. Biological markers such as peptides, proteins, metabolites, nucleic acids and polymorphisms have been proposed as novel exciting biomarkers. Patents have been filed demonstrating altered levels of proteins such as pancreatic polypeptide in beta cell failure and fibronectin and futuin-A in insulin resistance. Much interest has focused on the potential of glycosylated proteins such as glycated insulin, glycosylated amylin, C-terminally truncated form of the receptor for advanced glycation end-products, and glycated LDL antibodies. The emergence of genomic analysis is now complemented by systems biology and computational methods that can unravel large amounts of heterogeneous genetic and genomic information to produce meaningful results. Many patents have been filed that claim to estimate the susceptibility or predisposition of metabolic disease such as diabetes. New genomic technologies such as transcriptional profiling and proteomics have been shown to be significant in identifying and validating biomarkers, and systems biology has shown great promise in unravelling the complexities of genomic, proteomic and metabolomic technologies.

Ghrelin, a peptide predominantly produced by the stomach, was discovered as natural ligand of the Growth Hormone Secretagogue receptor type 1a (GHS-R1a) and was anticipated to play major role in the control of somatotroph function. Ghrelin progressively turned out to exert pleiotropic actions on several endocrine and non endocrine target tissues. Particular attention has focused on its central orexigenic effect and weight control, and more recently on its peripheral metabolic actions on insulin secretion and insulin sensitivity, glucose and lipid metabolism. Ghrelin circulates in two forms, acylated (AG) and unacylated (UAG). Interestingly, some metabolic actions of ghrelin are independent of its acylation, which is necessary for it to bind and activate the GHS-R1a, supporting the hypothesis of the existence of several ghrelin receptor subtypes involved in the control of metabolic functions and pancreatic cell survival. Recent data have introduced the hypothesis that the ghrelin system plays a role in polygenic obesity, type 2 diabetes, metabolic syndrome, atherogenesis, and β-cell survival in type 1 diabetes. Many experimental studies have recently tried to inhibit or amplify ghrelin secretion for the treatment of obesity and wasting syndromes, respectively. This review recapitulates what is known about ghrelin chemical structure, GHS-R1a and the putative unknown receptor subtypes, AG and UAG involvement in the control of feeding, weight, glucose and lipid metabolism, and the recently patented molecules that modulate the pleiotropic actions of the ghrelin system.

The medical treatment of patients diagnosed with anaplastic thyroid cancer (ATC) is not standardized, and it is almost always used in combination with surgery. Novel treatment strategies are necessary to make progresses in treating ATC. Promising future directives include the possibility offered by peroxisome proliferator-activated receptor γ (PPARγ) agonists. PPARγ are members of a superfamily of nuclear hormone receptors. Activation of PPARγ isoforms elicits both antineoplastic and anti-inflammatory effects in several types of mammalian cells. Ligands for PPARγ induce apoptosis and exert antiproliferative effects on several carcinoma cell lines, and PPARγ agonists inhibit cell growth of some types of human thyroid cancer. We have recently evaluated the antiproliferative effect of PPARγ agonists in primary cultured cells from human ATC (ANA) patients. The results of this study demonstrated that PPARγ ligands thiazolidinediones (TZD) exert a significant antiproliferative effect in primary ATC cells, therefore TZD could be promising therapeutic agents for the treatment of patients who fails to respond to traditional treatments. The use of antiproliferative tests in ANA cells obtained from each patient may help in detecting responsive patients, in preventing the administration of inactive drugs to those unresponsive, and in comparing the antiproliferative effect of different drugs. This article also reviews some patents related to the field.

As the epidemic of obesity continues to infest the world population at alarming proportions, researchers have started to focus on the endocrine aspect of its basic unit: the adipocyte. The last two decades have proved beneficial in understanding the impact of adipocytes, specifically the metabolic influences of its hormones, the adipocytokines. This review focuses on our current understanding of leptin and adiponectin, two of the most studied and established adipocytokines. Patents regarding leptin and adiponectin are highlighted.

Lysophosphatidic acid (LPA) and its specific G-protein-coupled receptors have mitogen-like activities in cellular signal transduction. At the intracellular level, LPA is produced by phospholipase A1 (PLA1) or PLA2; at the extracellular level, LPA is produced by autotaxin/lysophospholipase D. Lipid phosphate phosphatases (LPPs) dephosphorylate LPA and thereby attenuate LPA signaling. Chronic kidney diseases (CKDs) and end-stage renal disease (ESRD) are significant public health issues throughout the world. In these conditions, there is a production and accumulation of transforming growth factor (TGF-β) and connective tissue growth factor (CTGF), leading to accumulation of extracellular matrix proteins and renal fibrosis. In addition, CKD risk factors such as diabetes mellitus, hypertension, dyslipidemia, and activation of the renin-angiotensin- aldosterone system can lead to overexpression of the TGF-β-CTGF-collagen/fibronectin axis and thereby accelerate formation of renal fibrosis. More than five LPA receptors (LPA1 - LPA5) have been identified and have been shown to be expressed in different tissues. LPA1 mediates lung and renal fibrosis following injury, and Ki16425 has been shown to be an antagonist of the LPA1 receptor and an attenuator of fibrosis formation. In this review, we provide a brief update on the concepts of renal fibrosis and the pathogenetic roles of the different LPA signaling pathways, discuss some recent patents on pharmaceuticals that disrupt these pathways, and introduce some pilot studies that have explored the therapeutic potentials of LPA receptor antagonists for management of renal fibrosis.

Despite advances in the development of anti-diabetic agents and a greater focus on cardiovascular risk modification for patients with diabetes, cardiovascular disease remains the most common complication of type 2 diabetes. Coronary artery disease and atherosclerosis are cardiovascular disorders with endothelial dysfunction that are associated with increased circulating levels of inflammatory markers. Endothelial dysfunction is currently through to be not only a marker of vascular disease, but also to play an important role in atherosclerosis. Thiazolidinediones (TZDs), which activates peroxisome proliferators-activated receptor gamma (PPAR-γ), are a class of antidiabetes agents. PPAR-γ activation prevented coronary arteriosclerosis by its antiinflammatory effects. Some studies demonstrated that TZDs reduce restenosis after coronary stenting. Recent study demonstrated that treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis in patients with type 2 diabetes and coronary artery disease. The PROactive study has suggested that the efficacy of pioglitazone reduces mortality in type 2 diabetes mellitus on the secondary endpoints. Recent study showed that pioglitazone treatment resulted in significant risk reduction in major adverse cardiac events in patients with advanced type 2 diabetes at high risk for cardiovascular events. TZDs improve endothelial dysfunction, prevent atherosclerosis, and significantly reduce the risk of cardiovascular disease. Some of the recent patent related to the field also discuss in this review article.

Both diabetes and Alzheimer's disease are growing problems in the world and have substantial impact on the quality of life. They share a number of common features. Usually diabetic patients are not routinely assessed for cognitive function. Several studies have linked dementia to diabetes. However, some studies have found no link between diabetes and dementia. In addition to the duration of diabetes, hypertension, dyslipidemia, small vessel diseases of brain, APOE, defect in cerebral insulin receptors signaling and role of insulin like growth factorI (IGF I) and insulin degrading enzymes (IGF I) have been postulated as possible mechanism for the cognitive decline in diabetes. Recently, several studies have been done to co relate the direct effect of insulin on brain. Studies have shown that insulin is required for learning and memory. Insulin affects the metabolism of Aβ (Amyloid beta) and tau proteins, the building blocks for amyloid plaques and neuro fibrillary tangles in the brain, the major pathological findings of Alzheimer's disease. Based on these facts, drugs like statins, anti diabetic drugs etc have been tried. The preventing measures should include control of diabetes, vascular risk factors and therapy directed towards insulin metabolism. More studies are required to find the exact pathophysiological mechanism of cognitive decline in diabetes, so as to have a therapeutic intervention at the appropriate time and prevent the cognitive dysfunction and thereby reduce the burden of the disease and health care costs. In this review the possible pathophysiology linking diabetes and cognitive dysfunctions and possible therapeutic interventions are discussed. This review also discusses some recent patents related to the field.

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