Estrogen receptor ligands: Design and synthesis of new 2-arylindene-1-ones
Department of Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA.Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 07/2005; 15(12):3137-42. DOI: 10.1016/j.bmcl.2005.04.013
The syntheses of a series of 2-arylindene-1-ones as potent ligands of ERbeta and ERalpha are described. Several compounds exhibited high potency and moderate selectivity for the ERbeta receptor. X-ray and modeling studies were used to understand ligand binding orientation and observed affinity.
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ABSTRACT: A new series of N-hydroxyethylpyrazole (12a–f) and N-hydroxymethylpyrazole derivatives (15a–f) were designed for their estrogenic activities, having a 11.0 ± 0.5 Å distance between their two hydroxyl groups, aliphatic–OH and phenolic–OH similar to 17β-estradiol (E2) as an endogenous hormone. To synthesize the title compounds, the key intermediate 1,3-dicarbonyl derivatives (2 and 8), were treated with hydrazine hydrate to produce the pyrazole ring 5 and 9. Further hydroxyalkylation of the latter produced the title pyrazoles. The position of hydroxyethyl or hydroxymethyl substituents in the products was determined through 2D NOE NMR spectroscopy.
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ABSTRACT: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting more than 4 million Americans, and it is a huge drain on health care resources. Moreover, the cost burden of AD will increase substantially without the development of drugs that prevent its onset or slow its progression. At the present time, the available AD drugs provide, at best, temporary cognitive improvement, and cost-benefit analyses indicate no more than marginal support for their use. AD is a disorder of complex etiology that is characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain. The Amyloid Cascade model of AD neurodegeneration postulates that the primary disease process is the deposition of amyloid plaques and their subsequent effects on cognition. However, as we review here, the emerging evidence argues against simple linear models of neurodegeneration in AD patients, and more complex models of etiology and pathogenesis are needed as part of the drug development process. As one potential therapeutic approach, there is substantial evidence that estrogens are neuroprotective and act on a number of neural pathways, many of which are compromised in AD. A number of studies have shown that estrogens provide clinical benefit in AD patients and in other neurodegenerative disorders. Unfortunately, the negative results of the Women's Health Initiative Memory Study (WHIMS) have overshadowed the positive results from the last four decades. However, as discussed here, there are a number of reasons why the WHIMS results should not be generalized. On balance, estrogens remain a fruitful drug development approach for AD, and other neurodegenerative conditions, and especially those estrogen compounds or analogues that avoid or minimize the complications associated with long-term use of feminizing hormones in post-menopausal women. Drug Dev. Res. 66:53–77, 2006. © 2006 Wiley-Liss, Inc.
Article: Estrogen receptor modulator review[Show abstract] [Hide abstract]
ABSTRACT: The past few years have seen considerable advances in the development of estrogen receptor (ER) modulators and in the understanding of their interaction on estrogen pathways. Whilst prototypical steroidal estrogen agonists have long been appreciated for their use in female contraception and estrogen replacement therapy, more recent investigations have focused on subtype estrogen receptor modulators with selectivity for use in rapidly expanding treatment modalities. As estrogenic effects are primarily mediated through two receptors, defined as ERα and ERβ, significant interest has been dedicated to identifying subtype-selective agonists, antagonists and selective estrogen receptor modulators (SERMs). Additional effort has been dedicated to finding non-subtype-selective SERMs with new utility or improved profiles. Many of these recently identified ligands represent real advances in terms of their preclinical profile with the potential to one day provide novel treatments. This review highlights recent developments on the structural and biological data reported for ER modulators in the patent and scientific literature during the period 2003 – 2005.
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