Current Topics in Medicinal Chemistry - Volume 3, Issue 14, 2003

Over the last several years, the nuclear hormone receptor superfamily has enjoyed a renaissance as a target of pharmaceutical research. These ligand-gated transcription factors regulate a plethora of biological activities and exert key roles in the pathophysiology of major disease states including diabetes, obesity, osteoporosis, inflammation, atherosclerosis, and congestive heart failure, just to name a few. The utilization of nuclear hormone receptor ligands as pharmacological agents dates at least to the early part of the 20th century, when the hormonal components of glandular extracts were first isolated and characterized. During the 1950s and 60s, pharmaceutical investment in the steroids was at its heyday, leading to the development of contraceptives, anti-inflammatory drugs, anabolic agents, and hormone replacement therapies. Gradually the emphasis began to shift toward steroid receptor antagonists and nonsteroidal ligands, particularly in the area of cancer research. With the development of molecular biology in the 1980s and 90s, techniques for the cloning, expression, purification, and sequencing of the receptor proteins began to appear. These tools allowed a more critical dissection of the elements of biological activity, and for the first time, the signaling mechanisms of nuclear hormone receptors began to be elucidated. The possibility that particular ligands might discriminate between the positive and negative effects of the steroids was advanced, culminating with the development of the first Selective Estrogen Receptor Modulators (SERMs). At the same time, new members of the nuclear hormone receptor superfamily were being identified, spawning significant research investment in anticipation that they might also serve as pharmacological targets. Indeed the PPAR's, early members of this “orphan” receptor group, were found to be the molecular target for the fibrates and the thiazolidinediones. The complete sequencing of the human genome has now defined the total number of members of the nuclear receptor family at 48. At the time of this writing, natural or synthetic ligands have been described for approximately 30 of these proteins. The application of modern methods of compound screening and structural biological techniques has greatly augmented our ability to identify ligands for the orphan receptors, and enabled the determination of their innate pharmacology. The reviews in this edition highlight some of the most important areas of current pharmaceutical research on nuclear hormone receptors. In each case, whether classical steroid receptors, orphan receptors, or structural biology, the clear message is that we are still very early in our understanding of these drug targets. The opportunities for pharmaceutical development continue to grow and will provide a fertile area for scientific research throughout the foreseeable future.

The natural calcium-regulating hormone 1α,25-dihydroxyvitamin D3 (1,25D3) is a secosteroid that offers organic chemists many sites for modifying structural and / or functional groups. Such modifications alter the chemistry, stereochemistry, and biological properties of the natural hormone. The resulting deltanoids (vitamin D analogs) have been used in the past two decades as molecular probes to investigate structure-function relationships based on their interactions with proteins that regulate deltanoid biostability (catabolic enzymes of the vitamin D endocrine system and vitamin D binding protein) and deltanoid transduction of biological activities (nuclear and membrane receptors). In this review we will focus on structural modifications of 1,25D3 that selectively modulate the nuclear vitamin D receptor (VDR). We will discuss the structural requirements and modifications that create analogs with greater potency and efficacy than the natural hormone (superagonists). We will also identify the structural features of an emerging group of noncalcemic selective agonists and describe the pharmacokinetic properties and VDR-mediated actions that promote their tissue- and gene-selective responses. In addition, we will speculate on the possible structural requirements for vitamin D antagonists. We will also examine the evidence from studies in cell-free systems, in culture and in vivo that explain the mechanisms for the distinct actions of each group of analogs, with special emphasis on the relationship between their mode of interaction with the VDR and the molecular and cellular outcome of these interactions. Finally, we will describe the current and potential use of these selective modulators of the VDR for treatment of human diseases such as osteoporosis, cancer, and secondary hyperparathyroidism.

Small molecules such as retinoids, steroid hormones, fatty acids, cholesterol metabolites, or xenobiotics are involved in the regulation of numerous physiological and patho-physiological processes by binding to and controlling the activity of members of the nuclear receptor (NR) superfamily of transcription factors. In addition to natural ligands, synthetic agonists or antagonists have been identified that in some cases specifically target NR isotypes, or elicit tissue- , signaling pathway-, or promoter-selective transcriptional responses. For these ligands the term ‘selective NR modulators’ (SNRMs) has been introduced. Structure determination of apo- and holo-NR ligand-binding domains (LBDs) - some of them complexed to small coactivator or corepressor fragments - revealed the major principles of ligand-dependent NR action and determinants of (isotype-) selective ligand binding. These studies also stimulated the interpretation of tissuespecific effects of SNRMs on wild-type or mutant receptors. In contrast to the increasing knowledge on the structureactivity relationship of NRs with known SNRMs, rather basic questions remain about the regulation of orphan NRs (for which no ligands are known) or ‘adopted’ orphan NRs (for which only recently ligands were identified). Several crystal structures of orphan NR LBDs uncovered unexpected properties, contributed to the understanding of orphan NR function, and may in the future permit the identification or design of ligands. This review will (i) focus on the current understanding of the structure-activity relationship of NR-ligand interactions, (ii) discuss recent advances in the field of ‘orphan’ NR crystallography, and (iii) outline future challenges in NR structural biology.

Thyroid hormone regulates many important processes in vertebrates. Analysis of the symptoms that accompany hypo- and hyperthyroidism, the most common disorders of the thyroid, suggests that there are certain desirable biological effects brought about by an excess or deficiency of thyroid hormone, and that selective thyroid hormone receptor modulators (STRMs) would be potentially useful therapeutic agents. This review will provide an introduction to thyroid hormone biology, and will discuss the chemistry and pharmacology of the first generation STRMs.

Glucocorticoids have a pervasive role in human health and physiology. The endogenous members of this family are involved in a breadth of endocrine functions including metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance, as well as maintenance of immunological, renal and skeletal homeostasis. The predominant mode of action of glucocorticoids involves regulation of gene expression via the glucocorticoid receptor (GR). Synthetic glucocorticoids have long been the standard for the treatment of inflammatory and immune disorders, yet the benefits of classic steroids such as dexamethasone and prednisolone are accompanied by well-characterized potentiation of homeostatic endocrine functions, leading to the side effects associated with prolonged treatment. In recent campaigns for safer analogs, compounds have been sought which differentiate functional repression of existing transcription factors such as AP-1 and NFκB from GR-mediated transcriptional activation arising from binding at glucocorticoid-receptor response elements (GREs). Such differentiated ligands would provide the desired immunoregulatory actions without the endogenous changes in gene expression associated with undifferentiated steroids. We detail the methods for the evaluation of selective GR modulators and describe the evolution of new compounds where varying degrees of selectivity have been reported.

Nuclear hormone receptors are ligand-activated transcription factors that regulate gene expression and play a critical role in endocrine signaling. Orphan nuclear receptors belong to this gene super-family but their target genes and physiological function have not been completely elucidated. In recent years, the identification of natural ligands for these orphan receptors, their expression pattern in different tissues and studies with knock-out animals has delineated distinct regulatory functions for these proteins. The orphans belonging to the PPAR, LXR and FXR family function as lipid and bile-acid sensors while PXR and CAR function as xenobiotic sensors. This review will describe the discovery of natural and synthetic ligands for a number of these orphan receptors (excluding the PPARs) and the identification and characterization of novel signaling pathways and new hormone response systems linked to these targets. Small-molecule modulators of LXR and FXR control key genes involved in cholesterol and lipid metabolism. PXR is a highly promiscuous xenosensor that responds to xenobiotic ligands (antibiotics, statins, glucocorticoids) and induces the Cyp3A gene, thereby playing a role in hepatoprotection and bile acid metabolism. A related receptor from the gene subfamily, CAR, displays high ligand selectivity and modulation of its activity in humans may significantly alter metabolism of drugs and other xenobiotics. The role of the ER relatives, the ERRs will become more apparent as ligands are identified and linked to target genes and physiological function. These targets offer multiple opportunities for therapeutic intervention with small-molecule drugs, in diseases related to neuronal function, inflammation, lipid homeostasis, metabolic function and cancer.

As master regulators of lipid metabolism the peroxisome proliferator activated receptor (PPAR) family controls a wide variety of cellular processes, and thus it is not surprising that a large effort has focussed on discovering agents to pharmacologically modulate activity of these receptors. Early generation PPAR ligands, such as the fibrates and the thiazolidinediones (TZDs), were discovered empirically through an in vivo structure activity relationship exercise, whereas currently PPAR ligands are more often identified through target based structural design using cloned and expressed receptors. Regardless of how they were discovered, the development and clinical use of PPAR ligands throughout the last decade has greatly advanced understanding of the physiological function and therapeutic value of modulating these receptors. This review will briefly examine the PPAR family and then outline in greater detail select PPAR ligands indicated for the treatment of metabolic disorders.

The estrogen receptor is a regulator of a wide range of physiological functions, including the female reproductive system, in addition to bone, cardiovascular and CNS function. ER ligands have been approved for the treatment of menopausal symptoms, breast cancer and osteoporosis, however the search continues for new modulators of ER function with improved properties. Progress in medicinal chemistry programs has resulted in the identification of structurally diverse molecules with unique biological properties. Recent advances in the design and synthesis of these non-steroidal and steroidal estrogen receptor ligands is reviewed. The relationship between the structural features of the ligand and receptor function is also discussed.