Synthesis and activities of anti-aldosterones

Laurent, Henry; Bittler, D.; Hofmeister, Helmut; Nickisch, Klaus; Nickolson, Robert; Petzoldt, Karl; Wiechert, Rudolf

doi:10.1016/0022-4731(83)90010-9

Cited by 21 publications

(14 citation statements)

References 8 publications

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“…1) was found to possess in vivo activity on the urinary Na + /K + ratio on average 8.6 times higher than spironolactone in rats although its affinity for rat renal cytoplasmatic MR preparations was only 0.73 times the affinity of spironolactone (Casals-Stenzel et al 1984). Spirorenone showed practically no affinity for the rat androgen receptor, but was found to have higher affinity for the progesterone receptor from estrogen-primed rabbit uterus than spironolactone (Laurent et al 1983). Single-dose administration of spirorenone to healthy individuals demonstrated that spirorenone was at least 4 times as potent as spironolactone with respect to urinary sodium excretion (Seifert et al 1982).…”

Section: Steroidal Mras (The First 45 Years Of Mra Randd)mentioning

confidence: 92%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

Kolkhof

Bärfacker

2017

Journal of Endocrinology

191

165

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The cDNA of the mineralocorticoid receptor (MR) was cloned 30 years ago, in 1987. At that time, spirolactone, the first generation of synthetic steroid-based MR antagonists (MRAs), which was identified in preclinical in vivo models, had already been in clinical use for 30 years. Subsequent decades of research and development by Searle & Co., Ciba-Geigy, Roussel Uclaf and Schering AG toward identifying a second generation of much more specific steroidal MRAs were all based on the initial 17-spirolactone construct. The salient example is eplerenone, first described in 1987, coincidentally with the cloning of MR cDNA. Its launch on the market in 2003 paralleled intensive drug discovery programs for a new generation of non-steroidal MRAs. Now, 30 years after the cDNA cloning of MR and 60 years of clinical use of steroidal MRAs, novel non-steroidal MRAs such as apararenone, esaxerenone and finerenone are in late-stage clinical trials in patients with heart failure, chronic kidney disease (CKD), hypertension and liver disease. Finerenone has already been studied in over 2000 patients with heart failure plus chronic kidney disease and/or diabetes, and in patients with diabetic kidney disease, in five phase II clinical trials. Here, we reflect on the history of the various generations of MRAs and review characteristics of the most important steroidal and non-steroidal MRAs.

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Section: Steroidal Mras (The First 45 Years Of Mra Randd)mentioning

confidence: 92%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

Kolkhof

Bärfacker

2017

Journal of Endocrinology

191

165

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“…The solvent was evaporated in vacuo and the crude was purified by column chromatography using 30% of EtOAc in hexane to get 0.86 g (96%) of compound 10; mp 188-189°C; FT IR (ATR, cm À1 ): 3517. 3 2.2.8. 17b-Hydroxyl-3b-methoxy-19-nor-17a-pregn-1,3,5(10)-triene-20-yn-21-ethyloate (12) Following the procedure described for the synthesis of compound 2, compound 11 (5 g, 17.5 mmol) was reacted with ethyl propiolate (8.6 g, 87.9 mmol) and LiHMDS (293 mg, 0.13 mmol) for 1 h. The crude was purified by column chromatography using 30% of EtOAc in hexane to get 6.3 g (95%) of compound 12 2.2.9.…”

Section: B-hydroxy-17a-pregn-5-ene-2117-carbolactone (10)mentioning

confidence: 98%

“…1). Drospirenone is a close analog of the diuretic spironolactone which was synthesized by Wiechert and coworkers as part of a program to find aldosterone antagonists [2][3][4][5][6]. Drospirenenone has antiminerelocorticoid as well as anti-androgenic properties and together with ethinyl estradiol it is marketed as an oral contraceptive called Yasmin Ò .…”

Section: Introductionmentioning

confidence: 99%

A new approach towards the synthesis of drospirenone and steroidal spirolactones

et al. 2015

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“…The following patents and publications [80][81][82][83], which differ slightly from one another, disclose similar processes for preparing drospirenone and are presented in Scheme 27.5.…”

Section: Scheme 274 Synthesis Of Drospirenonementioning

confidence: 99%