New Selective Inhibitors of Steroid 11β-Hydroxylation in the Adrenal Cortex. Synthesis and Structure–Activity Relationship of Potent Etomidate Analogues

Zolle, I.; Berger, Michael L.; Hammerschmidt, Friedrich; Hahner, Stefanie; Schirbel, Andreas; Peric-Simov, Biljana

doi:10.1021/jm800012w

Cited by 45 publications

(36 citation statements)

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“…We then asked if endogenous Gcrt signaling was also involved in the induction of Cer1 expression by treating differentiating mESC cultures with Etomidate (Eto), a Gcrt production inhibitor that prevents activity of Cyp11b1, a key enzyme in Gcrt production (Wagner et al, 1984; Zolle et al, 2008). Eto (10µM) given at day 3 exclusively blocked Cer1 expression, but did not affect other VE markers (Figure 2F).…”

Section: Resultsmentioning

confidence: 99%

Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells

et al. 2015

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Summary Aside from its role in cell membrane integrity, cholesterol is a key component in steroid hormone production. The vital functions of steroid hormones such as estrogen, testosterone, glucocorticoids (Gcrts) and mineralocorticoids (Mnrts) in perinatal and adult life are well understood; however, their role during early embryonic development remains largely unexplored. Here we show that siRNA-mediated perturbation of steroid hormone production during mesoderm formation has important consequences on cardiac differentiation in mouse embryonic stem cells (mESC). Both Gcrts and Mnrts are capable of driving cardiac differentiation in mESC. Interestingly, the Gcrt receptor is widely expressed during gastrulation in the mouse, and is exclusively localized in the nuclei - and thus active - in visceral endoderm cells, suggesting that it functions much earlier than previously anticipated. We therefore studied Gcrt signaling in mESC as a model of the gastrulating embryo, and found that Gcrt signaling regulates expression of the transcription factor Hnf4a and the secreted Nodal and BMP inhibitor Cer1 in the early visceral endoderm. RNAi-mediated knockdown of Gcrt function blocked cardiomyocyte differentiation, with limited effects on other cardiovascular cell types including vascular endothelial cells and smooth muscle. Furthermore, the cardiogenic effect of Gcrts required Hnf4a and paracrine Cer1. These results establish a novel function for cholesterol-derived steroid hormones and identify Gcrt signaling in visceral endoderm cells as a regulator of Cer1 and cardiac fate.

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Section: Resultsmentioning

confidence: 99%

Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells

et al. 2015

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“…Recently, however, we succeeded in the development of highly active and selective CYP11B2 inhibitors 14À18 with in vivo activity. 19,20 Regarding CYP11B1 inhibition, the hypnotic and unselective CYP inhibitor etomidate was used as starting point for three investigations: Roumen et al discovered selective CYP11B2 inhibitors, 21 Zolle et al described CYP11B1 inhibitors without investigating selectivity, 22 and we discovered the first rather selective CYP11B1 inhibitors. 23 The best compound identified (1, Scheme 2) shows an activity comparable to the clinically administered ketoconazole but strongly exceeds its selectivity (IC 50 = 152 nM, a fairly good selectivity toward CYP11B2 (selectivity factor, sf =18) and no inhibition of CYP17 and CYP19).…”

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confidence: 99%

Optimization of the First Selective Steroid-11β-hydroxylase (CYP11B1) Inhibitors for the Treatment of Cortisol Dependent Diseases

Hille

Zimmer

Haupenthal

et al. 2011

ACS Med. Chem. Lett.

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ABSTRACT:CYP11B1 is the key enzyme in cortisol biosynthesis, and its inhibition with selective compounds is a promising strategy for the treatment of diseases associated with elevated cortisol levels, such as Cushing's syndrome or metabolic disease. Expanding on a previous study from our group resulting in the first potent and rather selective inhibitor described so far (1, IC 50 = 152 nM), we herein describe further optimizations of the imidazolylmethyl pyridine core. Five compounds among the 42 substances synthesized showed IC 50 values below 50 nM. Most interesting was the naphth-1-yl compound 23 (IC 50 = 42 nM), showing a 49-fold selectivity toward the highly homologous CYP11B2 (1: 18-fold) as well as selectivity toward the androgen and estrogen forming enzymes CYP17 and CYP19, respectively. KEYWORDS:Cushing's syndrome, metabolic syndrome, steroid hormone biosynthesis, steroid-11β-hydroxylase (CYP11B1), CYP11B2, selective inhibitors E ndogenous Cushing's syndrome is a hormonal disorder caused by prolonged exposure to excessive levels of circulating glucocorticoids; therefore, it is also called hypercortisolism. Most people develop central obesity and often diabetes and hypertension. In many cases, hypersecretion of ACTH is observed, which is caused by a pituitary adenoma (Cushing's disease). 1 Adrenocortical tumors are common reasons for ACTHindependent hypercortisolism. In many cases, surgical removal of the tumor or radiation therapy cannot be applied and patients require temporary or permanent medication. 2 However, application of the glucocorticoid receptor antagonist mifepristone triggers a massive secretion of cortisol which is probably caused by the hypothalamic pituitary feedback mechanism. 3 A decrease of glucocorticoid formation should be a better therapeutic option. The best target for such an approach is steroid-11β-hydroxylase (CYP11B1), an adrenal CYP enzyme catalyzing the last step in cortisol production, the hydroxylation of deoxycortisol in the 11β-position (Scheme 1). There are inhibitors of cortisol biosynthesis such as ketoconazole, etomidate, and metyrapone in clinical use. 4 However, all of them show severe side effects due to the fact that they are unselective.A challenge in the development of CYP enzyme inhibitors is the selectivity versus other CYP enzymes. In the past, we and others have developed selective inhibitors of steroidogenic CYP enzymes. Aromatase (estrogen synthase, CYP19) 5À8 and 17R-hydroxylase-C17,20-lyase (CYP17) inhibitors 9À12 are first line drugs for the treatment of breast cancer and upcoming therapeutics for castration refractory prostate cancer, respectively. In the case of adrenal CYP11B enzymes, selectivity is very difficult to achieve, as the homology between CYP11B1 and CYP11B2 (aldosterone synthase, Scheme 1) is very high (93%), 13 and for a long time it was considered impossible to obtain selective inhibitors. Recently, however, we succeeded in the development of highly active and selective CYP11B2 inhibitors 14À18 with in vivo activity. 19,20 Regarding CY...

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“…Although there is a high medical need for drugs interfering with excessive glucocorticoid formation resulting in Cushing's syndrome, there are only a few inhibitors of CYP11B1 described so far. 27 Because of their unselective action, their application is associated with severe side effects: The CYP19 inhibitor aminoglutethimide, metyrapone, the antimycotics ketoconazole and fluconazole, and the hypnotic etomidate are also inhibitors of other adrenal and gonadal cytochrome P450 (CYP) enzymes, and trilostane is a 3βHSD inhibitor. 28 In the present work, we report about the design, synthesis, and biological evaluation of the first selective (regarding CYP11B2, CYP17, and CYP19) inhibitors of human CYP11B1.…”

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confidence: 99%

“…Thus, the design strategy starting from the CYP11B2 selective etomidate was successful. While Zolle et al described chiral etomidate derivatives with a high affinity to rat adrenal membranes as well as strong inhibition of cortisol secretion without investigating selectivity issues, 27 the compounds described in this paper were examined for selectivity toward the most crucial steroidogenic CYP enzymes, and several were found to be selective. Funding Sources: UEH is grateful to the European Postgraduate School 532 (DFG) for a scholarship.…”

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confidence: 99%

First Selective CYP11B1 Inhibitors for the Treatment of Cortisol-Dependent Diseases

Hille

Zimmer

Vock

et al. 2010

ACS Med. Chem. Lett.

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Outgoing from an etomidate-based design concept, we succeeded in the development of a series of highly active and selective inhibitors of CYP11B1, the key enzyme of cortisol biosynthesis, as potential drugs for the treatment of Cushing's syndrome and related diseases. Thus, compound 33 (IC 50 = 152 nM) is the first CYP11B1 inhibitor showing a rather good selectivity toward the most important steroidogenic CYP enzymes aldosterone synthase (CYP11B2), the androgen-forming CYP17, and aromatase (estrogen synthase, CYP19). KEYWORDS Cushing's syndrome, steroid hormone biosynthesis, steroid-11β-hydroxylase, CYP11B1 inhibitor, CYP17, CYP19, CYP11B2, etomidate I t is well-known that steroid hormones are essential for a large number of vitally important physiological processes. However, they are also associated with life-threatening diseases. Application of hormone receptor antagonists or biosynthesis inhibitors are regarded as therapeutic methods of choice. The biosynthetic pathways contain several established and potential drug targets. In the last decades, aromatase (CYP19) inhibitors were developed and continuously improved. 1-4 Nowadays, second and third generation inhibitors are used as first line therapeutics for hormonedependent breast cancer. 5 Some 15 years ago, the first selective androgen synthase (CYP17) inhibitors were described, [6][7][8] and recently, their benefits for the treatment of castration refractory prostate cancer were demonstrated. 9 Research was not only focused on the formation of steroid hormones in their endocrine glands but also on their activation in the target cell. Inhibition of steroid 5R-reductase is clinically well-established for androgen-dependent diseases. 10-13 Experimental results with hydroxysteroid dehydrogenase (HSD) inhibitors are very encouraging for estrogen-and glucocorticoid-dependent diseases. [14][15][16][17][18] Until some years ago, selective inhibitors of mineralo-and glucocorticoids were not in the focus of research efforts. This was due to the fact that the sequence identity between aldosterone synthase (CYP11B2) and cortisol synthase (steroid-11β-hydroxylase, CYP11B1) is very high (93%), 19 and it was considered impossible to obtain selective inhibitors of one enzyme versus the other. Recently, however, we have been able to demonstrate that it is possible to selectively inhibit CYP11B2. [20][21][22][23][24] Further structural optimizations resulted in in vivo active compounds with selectivity factors (sfs) reaching 1000 with regard to CYP11B1. 25,26 They could be candidates for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis. Although there is a high medical need for drugs interfering with excessive glucocorticoid formation resulting in Cushing's syndrome, there are only a few inhibitors of CYP11B1 described so far. 27 Because of their unselective action, their application is associated with severe side effects: The CYP19 inhibitor aminoglutethimide, metyrapone, the antimycotics ketoconazole and fluconazole, and the h...

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New Selective Inhibitors of Steroid 11β-Hydroxylation in the Adrenal Cortex. Synthesis and Structure–Activity Relationship of Potent Etomidate Analogues

Cited by 45 publications

References 46 publications

Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells

Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells

Optimization of the First Selective Steroid-11β-hydroxylase (CYP11B1) Inhibitors for the Treatment of Cortisol Dependent Diseases

First Selective CYP11B1 Inhibitors for the Treatment of Cortisol-Dependent Diseases

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