Mini Reviews in Medicinal Chemistry - Volume 5, Issue 8, 2005

Nuclear receptor (NR) proteins are ligand-dependent transcription factors that belong to the superfamily of steroid/thyroid/retinoid/vitamin D receptors. NR family members play important roles in cell growth, differentiation, homeostasis, metabolism and development. NRs are modular proteins that contain three distinct functional domains. An Nterminal domain containing a ligand-independent activation function, AF-1, a middle zinc-finger containing DNA binding domain (DBD) and C-terminal ligand binding domain (LBD) that also harbors a ligand-dependent transactivation function, AF-2. The activity of NR proteins is modulated by ligand binding to their LBDs that results in a conformational change leading to either transactivation or transrepression of target gene expression in a cell/tissue and promoter/gene-context dependent manner. NRs are one of the best therapeutic targets since their activities could be modulated by small molecules, leading to subtle changes in gene expression in the desired direction and normalization of the altered physiological/pathological phenotype. In the past decade, a number of molecular, genetic, structural and pharmacological studies have contributed to increased understanding of the molecular pathways involved in NR action. These studies have identified not only novel mechanisms of NR action but also provided new disease targets for small molecule ligands. These studies in addition have yielded novel molecular assays for the rapid identification of compounds with the desired pharmacological profile and have helped set a stage for the rational design of the next generation of pharmaceuticals. There are 48 members of the NR superfamily in the human genome. Interestingly, all the NRs (except LXR), whose ligands are known, are successful therapeutic targets. Therefore, synthetic and/or natural ligands of steroid hormone receptors (AR, MR, PR and GR), RAR, RXR, VDR, TR and PPAR, are currently marketed drugs (Table I). Further, the involvement of even orphan NRs whose ligands have not been identified, and LXRs, in important physiological or metabolic processes provides the rest of NRs with a high level of validation as potential therapeutic targets. NR based drugs account for approximately 10-15% of the total worldwide pharmaceutical market. Most of these drugs are best currently available options for the treatment of conditions associated with significant morbidity and mortality. A number of these treatments are currently in vogue even though their use is accompanied by unwanted side effects. For example, although glucocorticoids (GR agonists), one of the most successful classes of pharmaceuticals, are widely used for the treatment of inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, etc.), their use is associated with osteoporosis, hyperglycemia, hypertension, sleep disturbances and psychosis. Similarly, topical corticosteroids cause skin thinning and tachyphylaxis and thus cannot be applied for generally more than two weeks. Therefore, there is an urgent need for the development of safer oral and topical glucocorticoids without the above-mentioned side effects. PPARγ ligands, Actos and Avandia, are medicines of choice for the treatment of type II diabetes but their use is accompanied by unwanted side effects of weight gain and edema. Further, widespread use and development of VDR ligands for osteoporosis and inflammatory indications is hampered by their undesired side effect of hypercalcemia/hypercalciuria. Increased biology of NR action has resulted in the elucidation of the mechanisms underlying therapeutic actions and side effects. Recently, considerable pharmaceutical research has been directed towards identifying efficacious NR ligands devoid of their classical side effects. While it is not possible to cover all the NRs in a single issue, here a number of leading drug hunters provide a glimpse in the drug discovery efforts on selected members of this superfamily (MR, PR, Retinoid Receptors, FXR, VDR, PPARs and LXRs). In this decade, we hope to see the emergence of novel drugs from some of these efforts.

The nuclear receptor for progesterone is a target for contraception and for several therapeutic indications. Progestin agonists and antagonists in clinical use mimic the steroidal backbone of the cognate ligand, progesterone. Thus, they have significant cross-reactivity with other steroid receptors. Recently, nonsteroidal progesterone receptor ligands have begun to appear in the literature. This review will describe the current status of research into these promising new chemical entities.

Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. In this review, we summarize the preclinical and clinical evidence supporting the beneficial effects of eplerenone (INSPRA™), a selective aldosterone blocker, in the treatment of hypertension and heart failure. We also review the current status in understanding the molecular mechanisms of action of the MR and its ligand. In addition, we compare the effects of eplerenone and spironolactone, a nonselective aldosterone blocker, on the transcriptional activity of MR and provide a molecular explanation for the improved side-effect profile of eplerenone compared with spironolactone.

The farnesoid X receptor (FXR) is a nuclear receptor expressed in tissues exposed to high concentrations of bile acids such as the liver, kidney and intestine and functions as a bile acid sensor. FXR regulates the expression of various transport proteins and biosynthetic enzymes crucial to the physiological maintenance of lipids, cholesterol and bile acid homeostasis. The concept of reverse endocrinology, whereby the receptor is identified first, followed by the identification of ligands and the sequential elucidation of the physiological role of the receptor has been widely used for a number of orphan nuclear receptors. The design of synthetic high affinity ligands acting via these receptors not only helps to decipher the function of the receptor, but also should lead to the development of novel and highly specific drugs. The bile acid receptor FXR is a perfect example where this strategy helped with understanding the role of this receptor in cholesterol and bile acid homeostasis. Regulation of FXR through small-molecule drugs represents a promising therapy for diseases resulting from lipid, cholesterol and bile acid abnormalities.

Liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily of ligandactivated transcription factors. Two LXRs (LXRa and LXRb) were initially characterized as orphan members of this superfamily with disparate patterns of tissue expression. These two receptors later were recognized as sterol-responsive with the ability to directly bind several oxysterol metabolites. Many LXR target genes have been identified that implicate these receptors in a variety of physiological processes including cholesterol transport and metabolism, glucose metabolism, and inflammation. Synthetic LXR ligands have been designed with the potential to treat disorders such as atherosclerosis and diabetes. In this review, we describe the potential utility of LXR ligands in the treatment of disease.

Peroxisome proliferator-activated receptors (PPARs) alpha, gamma and delta (beta) are ligandactivated transcription factors of the nuclear hormone receptor superfamily which have been shown to play key roles in maintaining glucose and lipid homeostasis. The physiological effects of several marketed drugs for the treatment of dyslipidemia (fenofibrate and gemfibrozil) and diabetes (rosiglitazone and pioglitazone) have now been shown to be mediated through PPARalpha and PPARgamma respectively. Over the past few years our understanding of how PPAR ligands and receptors modulate gene expression has greatly increased; this knowledge is being used to design even more potent and efficacious PPAR ligands for the treatment of diabetes, dyslipidemia, atherosclerosis and obesity. This review is a brief survey of the PPAR field which highlights recent progress, with an emphasis on new ligands with novel PPAR profiles, particularly compounds which are co-agonists of PPAα, γ and β (δ).

Retinoids have shown beneficial therapeutic effects in pre-clinical and animal models for multiple pathologic indications, however severe adverse effects, restricting dosage and efficacy of oral formulations limit their use in patients. The focus of this review includes the actual medicinal use of retinoids and chemical efforts to generate highly selective and less toxic synthetic retinoids.

1α, 25-dihydroxyvitamin D3 {1,25-(OH)2D3}, the biologically active form of vitamin D, is an important hormone that is critically required for the maintenance of mineral homeostasis and structural integrity of bones. 1,25-(OH)2D3 accomplishes this by facilitating calcium absorption from the gut and by a direct action on osteoblasts, the bone forming cells. Apart form its classical actions on the gut and bone, 1,25- (OH)2D3 and its synthetic analogs also possess potent anti-proliferative, differentiative and immunomodulatory activities. 1,25-(OH)2D3 exerts these effects through vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the superfamily of steroid/thyroid hormone/retinoid nuclear receptors. The presence of VDR in various tissues other than gut and bone, along with their ability to exert differentiation, growth inhibitory and anti-inflammatory action, has set the stage for therapeutic exploitation of VDR ligands for the treatment of various inflammatory indications and cancer. However, the use of VDR ligands in clinic is limited by their major dose-related side effect, namely hypercalcemia/hypercalciuria. Efforts are being undertaken to develop vitamin D receptor modulators (VDRMs) that are tissue-selective and/or gene-selective in their action and these ligands may exhibit increased therapeutic indices. This review explores the recent advances in VDR biology, non-secosteroidal VDR ligands and the current and potential clinical applications of VDR ligands in inflammation and cancer.