Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site.

Luz, J.G.; Carson, Matthew W.; Condon, Bradley; Clawson, David K.; Pustilnik, Anna; Kohlman, Daniel T.; Barr, R. J.; Bean, James S.; Dill, M. Joelle; Sindelar, Dana K.; Maletic, Milan; Coghlan, Michael J.

doi:10.1021/acs.jmedchem.5b00736

Cited by 31 publications

(10 citation statements)

References 47 publications

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“…7-Sulfonamidoindole moiety is a key substructure found in numerous biologically important compounds such as the tubulin polymerization and cell proliferation inhibitors ER-68394 ( 1 ), E-7070 ( 2 ), and compound 3 and the glucocorticoid receptor antagonist compound 4 . Indoles 1 , 2 , and 3 have potential for treatment of congestive heart diseases, and 4 lowers LDL while raising HDL in a hamster model of dyslipidemia (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Iridium(III)-Catalyzed Regioselective C7-Amination of N-Pivaloylindoles with Sulfonoazides

Tan

2016

J. Org. Chem.

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Direct C7-amination of N-pivaloylindoles has been achieved using a combination of [Cp*IrCl], AgNTf, and AgOAc as the catalyst and sulfonoazides as the nitrogen source. The reaction proceeded at room temperature to 80 °C to afford 7-sulfonamidoindoles in good to excellent yields. The reaction is broadly applicable to the C7-amination of a wide variety of 3-, 4-, 5-, and 6-substituted N-pivaloylindoles with either alkyl or aryl sulfonoazides.

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Section: Introductionmentioning

confidence: 99%

Iridium(III)-Catalyzed Regioselective C7-Amination of N-Pivaloylindoles with Sulfonoazides

Tan

2016

J. Org. Chem.

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“…C3-aryl indole scaffolds can also be found in many bioactive small molecules (Liu et al., 2000, Güzel et al., 2009, Luz et al., 2015). We hypothesized that the oxidative aromatization of carvone moiety in product could afford such scaffold.…”

Section: Resultsmentioning

confidence: 99%

Anticancer Molecule Discovery via C2-Substituent Promoted Oxidative Coupling of Indole and Enolate

Zhu

Tang

et al. 2019

iScience

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C2, C3-disubstituted indole is one of the most frequently encountered motifs in bioactive alkaloids and medicinal chemistry. Thus, developing novel, concise, and efficient access to it is highly desired in drug discovery. Herein, we present such an approach to this scaffold by direct oxidative coupling of C2-substituted indoles and enolates. Compared with indole bearing no C2-substituent, higher yields (up to 96%) were obtained for C2-substituted indoles in most cases. Mechanistic studies showed the reaction went through a Fe-chelated radical-anion oxidative coupling procedure promoted by C2-substituent on indole by two means: (1) stabilizing C2-radical intermediate during the reaction; (2) reducing indole homocoupling. This approach serves as a synthetic useful tool to quickly build up bioactive small molecule library of C2, C3-disubstituted indoles, and several products showed promising anticancer activities. Besides, indomethacin and its analogs were conveniently prepared in three-step sequence efficiently, indicating the potential application of our approach in medicinal chemistry.

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“…Compared to recently discovered synthetic nonsteroidal GR antagonists and allosteric inhibitors, − mifepristone ( 1 ) stands out for its potency. However, mifepristone is a partial AR agonist, and its agonistic activity is sufficient to stimulate the proliferation of CRPC LNCaP/AR-luc (LNAR) cells both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101)

Rew

Eksterowicz

et al. 2018

J. Med. Chem.

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The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.

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Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site.

Cited by 31 publications

References 47 publications

Iridium(III)-Catalyzed Regioselective C7-Amination of N-Pivaloylindoles with Sulfonoazides

Iridium(III)-Catalyzed Regioselective C7-Amination of N-Pivaloylindoles with Sulfonoazides

Anticancer Molecule Discovery via C2-Substituent Promoted Oxidative Coupling of Indole and Enolate

Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101)

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