Current Topics in Medicinal Chemistry - Volume 12, Issue 6, 2012

This issue of Current Topic of Medicinal Chemistry highlight several aspects of the medicinal chemistry of nuclear receptors and their relevance in drug discovery by collecting comprehensive reviews from outstanding investigators involved in the field and examines the biology of specific subfamilies of these ligand-activated regulatory factors that might have relevance in the therapy of a wide variety of human alignments. The nuclear receptor family contains a large group of transcription factors, with 49 members presently identified in the human genome. The activity of most nuclear receptors is mediated by the binding of small lipophilic ligands such as steroid and thyroid hormones, bile acids, fatty acids, and retinoids. Nuclear receptors are active as either homo- or hetero-dimers and regulate transcription by binding to response elements in the regulatory regions of target genes. Over the past two decades significant advances have been made in the understanding of the regulation of gene expression by these regulatory elements. In many cases, the characterization of the receptor has preceded the study of the function and the identification of a ligand. In the past few years, the ligands for these orphan receptors have been identified and in many cases have turned out to be products of normal metabolism. These receptors regulate a diverse collection of genes that control cell differentiation and growth, lipid and glucose metabolism, and immune functions. Examples of drugs acting on nuclear receptors are glitazones, targeting PPARγ, estrogens for hormone replacement therapy, antiestrogens for treatment of cancer, and various steroids for treatment of inflammatory disorders. Most of the drugs on the market that act through the modulation of nuclear receptor activity were developed with an incomplete understanding of the receptor that they target. In consequence, they have side effects due to lack of receptor specificity or tissue selectivity. Increased understanding of the structure and function of nuclear receptors and their role in health and disease makes it possible to improve existing therapies and to treat new disorders with novel, more precise drugs that target nuclear receptors. The article by Michael Pawlak, Philippe Lefebvre and Bart Staels from the INSERM UMR1011, Institut Pasteur de Lille, is focused on the “General molecular biology and architecture of nuclear receptors”. The article examines the general biology of nuclear receptors. Nuclear hormone receptors function as ligand-activated transcription factors, and thus provide a direct link between signaling molecules that control these processes and transcriptional responses. A large number of nuclear receptors have been identified through sequence similarity to known receptors, but have no identified natural ligand, and are referred to as “nuclear orphan”. The article describes the general molecular architecture of this family of ligand activated regulatory factors and how they impact on chromatin remodeling. The article by Albane le Maire, Susana Alvarez, Pattabhiraman Shankaranarayanan, Angel R de Lera, William Bourguet and Hinrich Gronemeyer from Starsbourg, entitled: “Receptors and therapeutic applications of RAR/RXR modulators” examines the biology of retinoic acid receptors (RARs). RXRs are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. The third review by Carsten Carlberg and Ferdinand Molnar from the University of Eastern Finland, Kuopio, Finland, entitled: “Current status of Vitamin D signaling and therapeutic potentials” is focused on the Vitamin D (Vit. D). Vitamin D and in particular its biologically most active metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are central endocrine molecules that influence many aspects of human physiology, which are not only the well-known calcium and phosphorus uptake and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. The review is focused on the latest insight into vitamin D signaling in context with the most prominent 1α,25(OH)2D3 analogues. The fourth review by Maria P. Menendez-Gutierre, Tamas Roszer, Mercedes Ricote from Madrid, entitled: “Biology and therapeutic applications of peroxisome proliferator-activated receptors” is focused on the biology of potential therapeutic applications of peroxisome proliferator-activated receptors (PPARs). Similar to RXRs and VDR, PPARα, β, γ/δ are ligand dependent transcription factors. The three mammalian PPARs are key regulators of fatty acid and lipoprotein metabolism, glucose homeostasis, cellular proliferation/differentiation and the immune response. PPARs are therefore important targets in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes mellitus, and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis, arthritis, chronic pulmonary inflammation, pancreatitis, inflammatory bowel disease, and psoriasis. The review gives an overview of PPAR functions and discusses the current and potential medical implications of PPAR ligands in various pathologies, ranging from metabolic disorders to cardiovascular disease, chronic inflammation, neurodegenerative disorders and cancer. The review by Dr. Andreea Ciudin, Cristina Hernandez, Rafael Simo mfrom Barcelona, entitled “Update on Cardiovascular safety of PPARgamma agonists and relevance to medicinal chemistry and clinical pharmacology” has examined the “dark side” of the highly successful class of drugs, the glitazones, that specifically targets the PPARγ and have been widely used in the treatment of diabetes. Based on available evidence, glitazones have shown similar effects on glycemic control, as well as a range of similar adverse effects. The article outlines the need for development of novel class of PPARγ ligands or, perhaps better, for development of PPARβ/δ. An approach to select the desirable therapeutic effects of the full PPARγ agonists, and eliminate the unwanted side effects is the development of the selective PPAR modulators (known as SPPARMs). Little differences between the full PPARγ agonists versus SPPARMs determine changes in the conformation of receptor which can lead to changes in cofactor recruitment and transcriptional regulation. The sixth review by Stefano Fiorucci, Angela Zampella and Eleonora Distrutti, from Perugia and Naples, entitled: “Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders” is focused on a family of nuclear receptors that specifically senses bile acids. Bile acids are the end-product of cholesterol breakdown and their concentration in the entero-hepatic tissues is sensed by several nuclear receptors, more specifically by the farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) and also by VDR. FXR agonists are currently under clinical investigations but their use associates with potential side-effects. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however the recent discovery of selective antagonists from marine sponges has ground the identification/development of specific FXR antagonists that are currently used in pre-clinical models of liver injury. The review is focused on the latest update in the identification of FXR and PXR agonists and antagonists and exploitation of their use in preclinical models of human pathologies. The article by Barbara Renga, Andrea Mencarelli, Sabrina Cipriani and Eleonora Distrutti all from Perugia, examines a novel field of interest in area of “Molecular determinants of Gastrointestinal and liver cancers: Role of Bile acid activated Nuclear Receptors”. The article examines the role of bile acids regulated nuclear receptors in regulating critical steps cell growth and differentiation and how bile acid-activated receptors could be involved in development of gastrointestinal cancers. The final review article of this issue by Maria Valeria d'Auria, Valentina Sepe and Angela Zampella, all from Naples, entitled: “Natural ligands for nuclear receptors: biology and potential therapeutic applications” is focused on the discovery of novel natural compounds, from marine and vegetal realms, targeting nuclear receptors and therefore useful for the treatment of a variety of diseases, such as cancer, diabetes, dyslipidemia, fatty liver disease, drug hepatotoxicity and cholestasis. As a guest Editor I wish to warmly thank all the authors who contributed articles in this Special Issue. I'm also grateful to each and every scientist who reviewed manuscripts for this Special Issue.

Nuclear receptors (NRs) regulate and coordinate multiple processes by integrating internal and external signals, thereby maintaining homeostasis in front of nutritional, behavioral and environmental challenges. NRs exhibit strong similarities in their structure and mode of action: by selective transcriptional activation or repression of cognate target genes, which can either be controlled through a direct, DNA binding-dependent mechanism or through crosstalk with other transcriptional regulators, NRs modulate the expression of gene clusters thus achieving coordinated tissue responses. Additionally, non genomic effects of NR ligands appear mediated by ill-defined mechanisms at the plasma membrane. These effects mediate potential therapeutic effects as small lipophilic molecule targets, and many efforts have been put in elucidating their precise mechanism of action and pathophysiological roles. Currently, numerous nuclear receptor ligand analogs are used in therapy or are tested in clinical trials against various diseases such as hypertriglyceridemia, atherosclerosis, diabetes, allergies and cancer and others.

Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies.

Vitamin D and in particular its biologically most active metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are central endocrine molecules that influence many aspects of human physiology, which are not only the well-known calcium and phosphorus up-take and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. Basically all actions of 1α,25(OH)2D3 are mediated by the transcription factor vitamin D receptor (VDR). The crystal structure of the VDR and detailed knowledge on its molecular interactions with the ligand provide significant insight into the mechanisms of vitamin D signaling. This applies also on the action of the huge number of synthetic 1α,25(OH)2D3 analogues, which have been developed with the goal of a therapeutic application in hyper-proliferative diseases, such as psoriasis, benign prostate hyperplasia and different types of cancer, in immune functions, such as autoimmune diseases and microbial infections, or in bone disorders, such as osteoporosis. Moreover, detailed investigations on many VDR target genes and in particular the recently available genome-wide view on vitamin D signaling allows a more complete view on the potential of the nuclear hormone. In this review we discuss the latest insight into vitamin D signaling in context with the most prominent 1α,25(OH)2D3 analogues.

Peroxisome proliferator-activated receptors (PPARs) are ligand dependent transcription factors. The three mammalian PPARs are key regulators of fatty acid and lipoprotein metabolism, glucose homeostasis, cellular proliferation/ differentiation and the immune response. PPARs are therefore important targets in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes mellitus, and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis, arthritis, chronic pulmonary inflammation, pancreatitis, inflammatory bowel disease, and psoriasis. Recent advances have attributed novel functions to PPARs in blood pressure regulation, neuroinflammation, nerve-cell protection, inflammatory pain reduction, and the hypothalamic control of metabolism. The abundant pleiotropic actions of PPARs suggest that PPAR agonists have enormous therapeutic potential. However, current PPAR-based therapies often have undesired side effects due to the concomitant activation of PPARs in non-target cells. There is therefore growing interest in the development of cell-specific PPAR agonists and improvement of the clinical use of PPAR ligands. This review gives an overview of PPAR functions and discusses the current and potential medical implications of PPAR ligands in various pathologies, ranging from metabolic disorders to cardiovascular disease, chronic inflammation, neurodegenerative disorders and cancer.

Peroxisome proliferator-activator receptors (PPARs) are now known as members of the nuclear hormonereceptor superfamily of ligand-activated transcription factors that regulate gene expression in response to nutritional and physiological stimuli. PPARγ plays a crucial role in glucose homeostasis and it is involved in the regulation of lipid metabolism and adipocyte differentiation and function. From all the PAARγ ligands, the thiazolidindiones (TZDs) are of most clinical importance. Rosiglitazone and pioglitazonehave been largely used so far in the clinical practice. They provide similar effects on glycemic control, as well as a range of similar adverse effects, such as weight gain, fluid retention, and increased risk of hearth failure, which seem to be PPARγ mediated. Interestingly, they differ on their effect on lipid and cardiovascular safety profile, indicating a PPARγ-independent mechanism. Indeed, rosiglitazone was recently withdrawn in Europe and its use has been restricted in USA as a consequence of increased risk of cardiovascular events in type 2 diabetic patients. This review is focused on the cardiovascular effects of rosiglitazone and pioglitazone as representative members of PPARγ ligands, because they were widely evaluated in many clinical trials and experimental studies and data obtained from these studies are relevant from medicinal chemistry and clinical pharmacology point of view. Finally, an overview on the development of selective PPARγ modulators and/or dual PPARα/γ agonists will be given. These new approaches might provide anti-hyperglycemic efficacy without the associated undesirable side-effects. However, further experimental and clinical studies evaluating the theoretical benefit and safety of this therapeutic strategy are needed.

The farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/ activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocyte's basolateral transporters. Because these effects might worsen liver injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however specific FXR antagonists that are currently used in pre-clinical models of liver injury have been identified from marine organisms. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to target subsets of genes in the intestine and liver avoiding sideeffects linked to FXR activation.

Invasion and metastasis are critical determinants of gastrointestinal and liver cancers morbidity. Genes and molecules participating in these steps (e.g. growth factors and their receptors, cell cycle regulators, cell adhesion molecules, matrix degrading enzymes) have been progressively clarified. Activated Wnt signaling pathway has been found in these tumors. Mutations in one of the DNA mismatch repair genes, alterations in epigenetics, such as aberrant DNA methylation and histone modifications are associated with the progression of gastrointestinal and control liver neoplasies. Bile acids (BAs), the main constituents of bile, activate a family of nuclear receptors (NRs) that control critical steps in bile acid homeostasis, endo- and xenobiotics detoxification, glucose, lipid metabolism and innate immunity. BAs activated NRs are misregulated in gastrointestinal and liver cancers. The present review provides an overview on the molecular determinants involved in gastrointestinal and liver cancers and focuses on the role of BAs activated NRs in the pathogenesis of these tumors.

Nuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics. Research in the last two decades has focused to the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases, such as cancer, diabetes, dyslipidemia, fatty liver disease, drug hepatotoxicity and cholestasis. The search for novel NRs agonists and antagonists with enhanced selectivity prompted the exploration of the extraordinary chemical diversity associated to natural products. In recent years a number of natural products were disclosed as ligands of NRs and proved to have remarkable affinity and in some cases peculiar mode of action. In this review the natural ligands of the subfamily NR1, NR2, and NR3 will be described with an emphasis to their mechanisms of action and pharmacological profiles.