(S)-N-{3-[1-Cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: A Potent, Nonsteroidal, Functional Antagonist of the Mineralocorticoid Receptor

Bell, Mike; Gernert, Douglas L.; Grese, Timothy A.; Belvo, Matthew D.; Borromeo, Peter S.; Kelley, Sally Ann; Kennedy, Joseph H.; Kolis, Stanley P.; Lander, Peter A.; Richey, Rachel N.; Sharp, V. Scott; Stephenson, Gregory A.; Williams, Jeffrey; Yu, Hannah; Zimmerman, Karen; Steinberg, Mitchell I.; Jadhav, Prabhakar K.

doi:10.1021/jm701186z

Cited by 43 publications

(25 citation statements)

References 8 publications

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“…An important consideration for the present findings is the potential off-target effects of spironolactone. While spironolactone is the MR antagonist most frequently used in the literature (Zhou et al, 2010, Zhou et al, 2011, Nasca et al, 2015), in addition to the MR (Ki = 2.32 nM) spironolactone is active at the glucocorticoid receptor (Ki = 32.6 nM), androgen receptor (Ki = 39.4 nM), progesterone receptor (Ki = 400 nM), and estrogen receptor (Ki > 1100 nM) (Bell et al, 2007). Therefore, while the spironolactone doses used in this study are within the range used in the literature (with the exception of 100 mg/kg), we cannot definitively conclude the contribution of these off target effects to the observed reductions alcohol self-administration and locomotor behavior.…”

Section: Discussionmentioning

confidence: 99%

The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats

Makhijani

Voorhies

Besheer

2018

Pharmacology Biochemistry and Behavior

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Cortisol/corticosterone and the hypothalamic-pituitary-adrenal (HPA) axis serve an important role in modulating alcohol drinking behaviors. To date most alcohol research has focused on the functional involvement of corticosterone and the glucocorticoid receptor (GR), the primary receptor for corticosterone. Recent studies have indicated that the related mineralocorticoid receptor (MR), which binds both corticosterone and aldosterone, may also play a role in alcohol drinking. Therefore, the purpose of the present study was to test the functional role of MR signaling in alcohol self-administration via pharmacological antagonism of the MR with spironolactone. Male and female Long-Evans rats were trained to self-administer a sweetened alcohol solution (15% (v/v) alcohol +2% (w/v) sucrose). The effects of spironolactone (0, 10, 25, 50 mg/kg; IP) were tested on alcohol self-administration and under "probe extinction" conditions to measure the persistence of responding in the absence of the alcohol reinforcer. Parallel experiments in sucrose self-administration trained rats were used to confirm the specificity of spironolactone effects to an alcohol reinforcer. In female rats spironolactone (50 mg/kg) reduced alcohol self-administration and persistence of alcohol responding. In male rats spironolactone (25 and 50 mg/kg) reduced alcohol self-administration, but not persistence of alcohol responding. Spironolactone reduced sucrose intake in female rats only, and locomotion in male and female rats during sucrose self-administration. There was no effect of spironolactone on persistence of sucrose responding. These studies add to growing evidence that the MR is involved in alcohol drinking, while underscoring the importance of studying both male and female animals.

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Section: Discussionmentioning

confidence: 99%

The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats

Makhijani

Voorhies

Besheer

2018

Pharmacology Biochemistry and Behavior

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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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“…One of them included a 3,3-bisaryloxoindol as central scaffold, where, for example, derivative 8 showed good selectivity over GR, PR, and AR (more than 390-fold) [31]. The other series contained an indole ring, as in compound 9, which was more potent than eplerenone in lowering blood pressure in a rat hypertension model [32]. A related series containing an indazole ring and an aryl sulfonamide were developed by Merck Sharp & Dohme Corp., for example, compound 10 (stereochemistry not disclosed) that showed a good PK profile in rats [33].…”

Section: Nonsteroidal Mr Ligandsmentioning

confidence: 99%

Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

Pérez-Gordillo¹,

Vega²,

Gerona‐Navarro³

et al. 2019

Aldosterone-Mineralocorticoid Receptor - Cell Biology to Translational Medicine

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The mineralocorticoid receptor (MR) belongs to the nuclear receptor superfamily and regulates body fluid and electrolyte balance. In the last years, much effort has been put into the development of non-steroidal MR antagonists that overcome the side effects of the marketed steroid drugs, and can be used for the treatment of hypertension and heart failure, among others. Initially, MR was identified in epithelial cells, however it also plays important roles in non-epithelial tissues. In this sense, it is of interest to discover ligands that might induce different MR conformational changes, leading to specific coregulator interactions, which could confer tissue-specific effects. Different series of non-steroidal ligands with diverse central scaffolds has been described, which shows antihypertensive and cardiorenal protective effects. This review covers a description of different non-steroidal MR antagonist families, with special focus on compounds under clinical development. The analysis of the three-dimensional (3D) structures of non-steroidal MR antagonists in complex with the MR ligand-binding domain (LBD), recently reported, highlights the interactions crucial for binding. The structure-activity relationships of known ligands, together with the insights provided by the 3D structures of ligand-LBD MR complexes, could help in the development of non-steroidal MR antagonists with improved properties.

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(S)-N-{3-[1-Cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: A Potent, Nonsteroidal, Functional Antagonist of the Mineralocorticoid Receptor

Abstract: A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.

Cited by 43 publications

References 8 publications

The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats

The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats

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

Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

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