Synthesis and Biological Evaluation of Novel, Selective, Nonsteroidal Glucocorticoid Receptor Antagonists.

Akritopoulou‐Zanze, Irini; Patel, Jyoti; Hartandi, Kresna; Brenneman, Jehrod B.; Winn, Martin; Pratt, John K.; Grynfarb, Marlene; Goos-Nisson, Annika; Geldern, Thomas W von; Kym, Philip R.

doi:10.1002/chin.200434116

Cited by 2 publications

(2 citation statements)

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“…The chromene core bears a structural resemblance to the PR antagonists that had been disclosed by Abbott and Ligand (vide supra) [31]. This series of GR antagonists demonstrated high GR binding affinity (IC 50 <10nM) and inhibited dexamethasone induced alkaline phosphatase (ALP) production with reported IC50's of less than 100 nM [33]. The second series incorporated structural elements of both the triaryl (28) and chromene (29) series.…”

Section: Glucocorticoid Receptor Antagonistsmentioning

confidence: 86%

Recent Progress in the Discovery of Novel Glucocorticoid Receptor Modulators

Takahashi¹,

Razavi²,

Thomson³

2008

CTMC

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Glucocorticoids have been used in modern clinical practice for over fifty years. Although they have demonstrated potent anti-inflammatory and immunosuppressive activities, their association with debilitating and life-threatening side effects has been a major drawback. Recent insights into glucocorticoid biology have lent support to the hypothesis that the glucocorticoid anti-inflammatory activities could be dissociated from their adverse side effects. Inspired by these biological findings, the search for dissociated glucocorticoid receptor agonists has intensified. Antag-onists of the glucocorticoid receptor that offer therapeutic benefits for the treatment of diseases such as diabetes have also been pursued. These efforts have been partly focused on the development of tissue, especially liver, selective glucocor-ticoid receptor antagonists, which are thought to have improved safety profiles. This review offers a summary of the research and development activities in this field and covers journal and patent publications from 2003 to March 2006.

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Section: Glucocorticoid Receptor Antagonistsmentioning

confidence: 86%

Recent Progress in the Discovery of Novel Glucocorticoid Receptor Modulators

Takahashi¹,

Razavi²,

Thomson³

2008

CTMC

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“…The chromene scaffold is present in a novel class of selective non-steroidal glucocorticoid receptor (GR) antagonists. 11 Moreover, chromenes containing substituents at the C-4 position may act as potent retinoic acid receptor a-selective antagonists 12 and 4-aryl-4H-chromenes have been recently identified as potent apoptosis inducers. 13 This justifies efforts to develop new more efficient synthetic procedures towards this class of compounds from readily available starting materials by simple procedures.…”

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confidence: 99%

4-Aryl- and 4-Vinyl-2,2-Dialkyl-3-chromenes from Tertiary 3-(o-Bromophenyl)propynols via a Palladium-Catalyzed Hydroarylation/Hydrovinylation-Cyclization Sequence

Arcadi¹,

Cacchi²,

Fabrizi³

et al. 2006

Synlett

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4-Aryl-and 4-vinyl-2,2-dialkyl-3-chromenes were prepared from tertiary 3-(o-bromophenyl)propynols and aryl iodides or vinyl triflates through a one-pot process, which involves the addition of t-BuONa, dppf and, where appropriate, fresh Pd(OAc) 2 to the crude mixture resulting from the hydroarylation or hydrovinylation step [Pd(OAc) 2 , Et 3 N, HCOOH, Bu 4 NCl, toluene]. In general, 4-aryl-and 4-vinyl-2,2-dialkyl-3-chromenes are obtained with high regioselectivity and overall yields range from satisfactory to high. Vinyl triflates tend to give higher yields than aryl iodides.The palladium-catalyzed hydroarylation and hydrovinylation of disubstituted alkynes with aryl and vinyl halides or triflates represents a valuable tool for the addition of a carbon sp 2 unit and a hydrogen to a carbon-carbon triple bond. 1 With unsymmetrical alkynes, steric and coordinating effects appear to play a major role in controlling the regioselectivity of the process. Solvents 2 and other reaction parameters such as temperature, the presence or absence as well as the nature of phosphine ligands, and the nature of the sp 2 donor have also been found to influence the regiochemical outcome. In general, the reaction is stereoselective and overall cis-addition derivatives are usually obtained as the main products. Therefore, the addition to alkynes with suitable nucleophilic and electrophilic centers close to the acetylenic system can be followed by a cyclization step. We have taken advantage of this addition-cyclization strategy to develop new versatile routes to substituted butenolides, 3 quinolines, 4 coumarins, and chromanols. 5More recently, we reported the synthesis of chromene derivatives through the hydroarylation/hydrovinylationcyclization of tertiary 3-(o-acetoxyaryl)-and 3-(o-benzoyloxyaryl)propynols. 6 Though this process gives good overall yields with a variety of aryl iodides and vinyl triflates, it requires a stepwise protocol involving the protection of the starting material, isolation of hydroarylation/ hydrovinylation products, deprotection of the phenolic oxygen, and cyclization. Therefore, considering the general trend towards improving the environmental acceptability of synthetic processes and that one of the more convenient strategies is limiting the number of distinct steps, we decided to investigate the development of a simplified one-pot procedure, with beneficial effects on costs, time, energy, raw materials, and waste.The presence of the 2,2-dimethyl-3-chromene motif in a variety of biologically active compounds has led to a continuing interest in the chromene ring system. 7 The 2,2-dimethyl-3-chromene motif is commonly found in potassium channel activators with smooth-muscle relaxant activity in a variety of cardiovascular and bronchopulmonary diseases (cromakalim, 9 and several other compounds with the 2,2-dimethyl-3-chromene moiety have been tested 10 ). The chromene scaffold is present in a novel class of selective non-steroidal glucocorticoid receptor (GR) antagonists. 11 Moreover, chromenes containing subs...

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Synthesis and Biological Evaluation of Novel, Selective, Nonsteroidal Glucocorticoid Receptor Antagonists.

Cited by 2 publications

References 1 publication

Recent Progress in the Discovery of Novel Glucocorticoid Receptor Modulators

Recent Progress in the Discovery of Novel Glucocorticoid Receptor Modulators

4-Aryl- and 4-Vinyl-2,2-Dialkyl-3-chromenes from Tertiary 3-(o-Bromophenyl)propynols via a Palladium-Catalyzed Hydroarylation/Hydrovinylation-Cyclization Sequence

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