Current Topics in Medicinal Chemistry - Volume 8, Issue 9, 2008

The human nuclear hormone receptor (NHR) family consists of 48 transcription regulators which, in turn, control a vast assortment of biological functions. Receptor activation occurs upon binding with a variety of both high- and low-affinity ligands including steroids, prostanoids, retinoids, Vitamin D, oxysterols and bile acids. Many of these receptors serve as the basis for clinical intervention and involve treatments for breast and prostate cancers, coronary heart disease, diabetes and osteoporosis. However, 40% of the receptors are classified as “orphan receptors” since their physiological functions and binding ligands are unknown. Due to the established ability to identify treatments for diseases associated with NHRs, targeting these receptors for drug discovery endeavors after they become deorphanized will likely become a reality. For now, the immensely complicated processes involving the interplay of NHRs, ligands, cofactors and repressors affecting gene regulation, either through repression or up-regulation, are challenging variables to control in laboratory settings. Adding to these issues is the fact that, in many cases, confirmation of the validity of cellular and animal models must wait as results from clinical trials unfold. This thematic issue of Current Topics in Medicinal Chemistry entitled “The Medicinal Chemistry of Agents Targeting the Nuclear Hormone Receptor” encompasses reviews of the most recent advances and solutions to many of the problems associated with developing drugs whose targets are the NHRs. These six articles focus on steroid or endocrine hormone receptors - glucocorticoid (agonists and antagonist), estrogen, progesterone - and the metabolic receptors PPAR and LXR. The reader will readily appreciate the high quality of scientific investigations that reveal some of nature's most tightly held secrets. Despite the complex webs of chemical and biological interactions, significant drug discovery advances are being achieved. I would like to acknowledge the authors for their substantial contributions to the field of NHR research and thank them for writing these comprehensive and informative reviews. Hopefully these articles will inspire others to continue investigating innovative approaches to NHR-based therapies that will be capable of intervening in serious and often life-threatening diseases.

The Peroxisome Proliferator-Activated Receptors-PPARα, PPARγ, and PPARδ--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways.

Steroidal glucocorticoids are widely prescribed for the treatment of a variety of inflammatory and autoimmune diseases. Although they are effective, the side-effects associated with chronic glucocorticoid treatment, such as osteoporosis and hyperglycemia, can severely limit their long-term use. Hence, there is a need to develop new effective anti-inflammatory agents for systemic use which are dissociated from their unwanted side effects.

Synthetic steroidal progestins and antiprogestins have been widely used for decades to treat many gynecological conditions. The concept of selective progesterone receptor modulators (SPRMs) has been developed in recent years to design new therapeutic agents that have desirable PR modulating activity with significantly reduced sideeffects or increased safety margin. This review describes medicinal chemistry progress of multiple nonsteroidal SPRM series based on a screening hit, 1,2-dihydro-2,2,4-trimethyl-6-phenylquinolinone.

The Liver X Receptors LXRα and LXRβ are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Seminal studies with genetic and chemical tools were instrumental in the elucidation of cholesterol metabolism, gluconeogenesis, inflammation, and lipogenesis as signaling pathways that are controlled by the LXRs. First generation non-steroidal LXR agonists show beneficial effects in multiple animals models of human disease yet have not progressed in the clinic due to deleterious side effects in the liver. Numerous reports have appeared in the the recent literature that disclose new LXR signaling pathways and the identication of novel LXR chemotypes that may show improved therapeutic indices. This review will provide a brief historical perspective but will primarily focus on recent advances in LXR biology and chemistry.

Selective Estrogen Receptor Modulators (SERMs) have been the subject of extensive medicinal chemistry efforts at several pharmaceutical companies, including Merck. The Merck effort produced a wide variety of SERMs including ER-?? selective antagonists and ER-?? agonists in addition to balanced (non-selective) analogs. This article will provide a broad overview of the Merck SERM medicinal chemistry effort as published in the literature through early 2008.

This review covers recent progress in the discovery of selective glucocorticoid receptor (GR) antagonists. Potential therapeutic applications of selective GR antagonists are described including the pharmacological rationale and, in some cases, clinical evidence that underlies these proposed uses. Disease areas that are discussed are Cushing's syndrome, psychotic depression, diabetes, obesity, Alzheimer's disease, neuropathic pain, drug abuse, and glaucoma. Methods for evaluating GR antagonist properties (binding, functional, and in vivo assays) are briefly covered. Early research on steroidal ligands which led to the identification of the non-selective GR antagonist RU-486 (mifepristone) and the GR-selective steroid RU-43044 is reviewed as is subsequent work on related steroidal compounds. Structure activity relationships (SAR) of nonsteroidal GR antagonists from the following structural classes are presented: octahydrophenanthrenes, spirocyclic dihydropyridines, triphenylmethanes and diaryl ethers, chromenes, dibenzyl anilines, dihydroisoquinolines, pyrimidinediones, azadecalins, and aryl pyrazolo azadecalins.

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