Original article
1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors

https://doi.org/10.1016/j.ejmech.2014.10.027Get rights and content

Highlights

  • Inhibition of aldosterone synthase is a superior treatment of cardiovascular diseases.

  • 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols were synthesized and evaluated.

  • These compounds are potent aldosterone synthase inhibitors (IC50 < 65 nM).

  • High selectivity over CYP11B1, CYP17 and CYP19 were achieved.

Abstract

1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11β-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.

Introduction

The mineralocorticoid aldosterone plays a crucial role in the salt and water homeostasis. Its release is mainly controlled by angiotensin-II via the renin-angiotensin-aldosterone system (RAAS) and potassium plasma levels. Chronically elevated plasma aldosterone levels are linked to the development and progression of certain cardiovascular diseases such as hypertension, congestive heart failure, and myocardial fibrosis [1]. In clinical studies, the mineralocorticoid receptor (MR) antagonists like spironolactone and eplerenone reduce mortality in patients with congestive heart failure and post acute myocardial infarction [2], [2](a), [2](b), thereby showing the detrimental role of aldosterone in the pathophysiology of cardiovascular diseases and the therapeutic benefit of blocking its action. However, the influence of the unaffected elevated plasma aldosterone levels leading to an up-regulation of mineralocorticoid receptor expression [3] and to nongenomic aldosterone effects is not yet fully explained [4]. Therefore, the mitochondrial cytochrome P450 enzyme aldosterone synthase has been highlighted as a potential pharmacological target, and it was proposed that CYP11B2 inhibitors could serve as drugs for the aforementioned cardiovascular diseases [5], [6], [7]. CYP11B2 is located in the zona glomerulosa of the adrenal cortex. It catalyzes the last steps in aldosterone biosynthesis, i.e. in humans the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone [8]. The inhibition of CYP11B2 reduces the production of aldosterone and is therefore a treatment option for related diseases.

In the development of CYP inhibitors, a crucial point is the selectivity over other CYP enzymes, especially steroidogenic and hepatic CYPs. The most challenging task is to achieve selectivity versus the highly homologous (>93%) [9] 11β-hydroxylase (CYP11B1), which plays a key role in glucocorticoid biosynthesis by catalyzing the formation of cortisol from 11-deoxycortisol [8]. Despite of these difficulties, selective inhibitors of CYP11B1 [10], [10](a), [10](b), [10](c), [10](d) and CYP11B2 have been successfully identified. Several classes of CYP11B2 inhibitors were derived from the anaesthetic R-etomidate or unselective CYP19 inhibitor fadrozole. For example, Hermans et al. describe a class of N-benzyl-1H-imidazoles [11], and several patents disclose, for example, imidazo[1,5]pyridine [12], 4-imidazolyl-1,2,3,4-tetrahydroquinoline [13] derivatives or heterocyclic spiro-compounds [14](b), [14](c), [14], [14](a) as aldosterone synthase inhibitors. One of these inhibitors, LCI699, has been investigated in clinical trials for the treatment of primary hyperaldosteronism and hypertension. However, in order to avoid the potential impairment of cortisol biosynthesis that could result from CYP11B1 inhibition by this compound, low doses (<1.3 mg daily) were applied, and consequently only moderate curative effects were observed [15](a), [15](b), [15].

In our group, in 2003 a drug discovery program based on a biological screening of known CYP inhibitors had been performed [5]. Utilizing the broad experience gained in the development of inhibitors of other CYP enzymes, such as aromatase (CYP19) [16](b), [16](c), [16], [16](a) or CYP17 [17](d), [17](e), [17], [17](a), [17](b), [17](c), several classes of nonsteroidal highly potent and selective hCYP11B2 inhibitors were obtained by subsequent optimization strategies, i.e. imidazolyl- and pyridylmethylenetetrahydronaphthalenes and -indanes [18], [19], heterocycle substituted naphthalenes, dihydronaphthalenes [20], [20](a), [20](b), [21], [22] and 3,4-dihydro-1H-quinolin-2-ones [23].

In this study, we describe the synthesis and biological properties of a series of 1-phenylsulfinyl-2hydroxy-3-pyridyl substituted naphthalenes and structurally related compounds (Chart 1). This class of compounds was obtained by oxidation of 1-(phenylthio)-3-(pyridin-3-yl)naphthalen-2-ols, which were readily accessible by a new SN,Ar reaction recently described by us [24]. The novel compounds revealed themselves as potent and selective CYP11B2 inhibitors. Structure activity relationships of different substituents on the phenylsulfinyl moiety were established considering the potency toward human and the selectivity versus human CYP11B1, CYP17 and CYP19. Compound 11 was further investigated in a pharmacokinetic study in male Wistar rats.

Section snippets

Chemistry

Recently, the synthesis of sulfides 1a–4a was described by us (Scheme 1) [24]. 2-Methoxynaphthalene is converted into the boronic acid via ortho-lithiation [25] and subsequently transferred into 3(3-methoxynaphthalen-2-yl)-pyridine by a Suzuki reaction [21], [26]. Cleavage of the methyl ether by refluxing in aqueous hydrobromic acid and reaction of the obtained alcohol with triflate anhydride led to intermediate 1b [23]. Reaction of the triflate 1b with substituted thiophenols or

Discussion and conclusion

This paper describes 1-phenylsulfinyl-3-(pyridin-3-yl)naphthalene-2-ols as a new class of potent and selective human CYP11B2 inhibitors.

3-(Pyridin-3-yl)naphthalene as the common sub-structure of all synthesized compounds has already been shown to be a potent CYP11B2 inhibitor [20]. This fact together with the comparison of the biological results of sulfides 1a-4a (18–22 % inhibition, c = 500 nM) with sulfoxides 14 (IC50 = 27–64 nM) exhibits the importance of the oxygen for CYP11B2 inhibition.

Chemical and analytical methods

Melting points were measured on a Mettler FP1 melting point apparatus and are uncorrected. 1H NMR and 13C NMR were recorded on a Bruker AM500 spectrometer 500 MHz and 125 MHz, respectively, at 300 K. Chemical shifts (δ) are reported in parts per million (ppm), by reference to the hydrogenated residues of the deuterated solvent as internal standard. All coupling constants (J) are given in Hertz (Hz). Mass spectra (LC/UV/MS: ESI) were recorded on a SpectraSystem/MSQ Plus (ThermoFinnigan)

Acknowledgment

The authors thank Gertrud Schmitt and Jeannine Jung for the help in performing the in vitro tests. We are grateful to Prof. J. J. Rob Hermans, University of Maastricht, The Netherlands, for supplying the V79MZhCYP11B1 cells, and to Prof. Rita Bernhardt, Saarland University, for supplying the V79MZhCYP11B2 cells. We thank Dr. M. Heydel for helpful discussions during writing the manuscript. The PK-study was conducted by Pharmacelsus GmbH financed by the grant 0315478A from BMBF Germany.

References (43)

  • C. Delcayre et al.

    Molecular mechanisms of myocardial remodeling. The role of aldosterone

    J. Mol. Cell. Cardiol.

    (2002)
  • P.B. Ehmer et al.

    Development of a test system for inhibitors of human aldosterone synthase (CYP11B2): screening in fission yeast and evaluation of selectivity in V79 cells

    J. Steroid Biochem.. Mol. Biol.

    (2002)
  • T. Kawamoto et al.

    Role of steroid 11β-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans

    Proc. Natl. Acad. Sci. U S A

    (1992)
  • E. Mornet et al.

    Characterization of two genes encoding human steroid 11β-hydroxylase (P-450 11β)

    J. Biol. Chem.

    (1989)
  • L. Roumen et al.

    Synthesis, biological evaluation, and molecular modelling of 1-benzyl-1H-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2)

    J. Med. Chem.

    (2010)
  • F. Firooznia

    Preparation of Imidazo[1,5a]pyridine Derivatives for Treatment of Aldosterone Mediated Diseases

    (2004)
  • Q.-Y. Hu et al.

    4-Imidazolyl-1,2,3,4-tetrahydroquinoline Derivatives and Their Use as Aldosterone Synthase/11-beta-hydroxylase Inhibitors

    (2008)
  • P. Herold et al.

    Heterocyclic Spiro-compounds as Aldosterone Synthase Inhibitors

    (2006)
    P. Herold et al.

    Heterocyclic Spiro-compounds

    (2006)
    P. Herold et al.

    Fused Imidazole Derivatives and Use Thereof as Aldosterone Synthase Inhibitors

    (2006)
  • J. Menard et al.

    Hormonal and electrolyte responses to the aldosterone synthase inhibitor LCI699 in sodium depleted healthy subjects

    J. Am. Coll. Cardiol.

    (2010)
    W.B. White et al.

    Blockade of aldosterone production as a novel approach to the management of high blood pressure: efficacy and tolerability of the aldosterone synthase inhibitor LCI699 in patients with stage 1-2 hypertension

    J. Am. Coll. Cardiol.

    (2010)
  • S. Gobbi et al.

    Imidazolylmethylbenzophenones as highly potent aromatase inhibitors

    J. Med. Chem.

    (2007)
    S. Gobbi et al.

    Modulation of cytochromes P450 with xanthone-based molecules: from aromatase to aldosterone synthase and steroid 11β-hydroxylase inhibition

    J. Med. Chem.

    (2013)
    M.P. Leze et al.

    Synthesis and biological evaluation of 5-[(aryl)(1H-imidazol-1-yl)methyl]-1H-indoles: potent and selective aromatase inhibitors

    Bioorg. Med. Chem. Lett.

    (2006)
  • U.E. Hille et al.

    Novel CYP17 inhibitors: synthesis, biological evaluation, structure–activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls

    Eur. J. Med. Chem.

    (2009)
    Q. Hu et al.

    Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17)-Part II: core rigidification and influence of substituents at the methylene bridge

    Bioorg. Med. Chem.

    (2008)
    L. Yin et al.

    Recent progress in pharmaceutical therapy for castration-resistant prostate cancer

    Int. J. Mol. Sci.

    (2013)
    R.W. Hartmann et al.

    Synthesis and evaluation of azole-substituted tetrahydronaphthalenes as inhibitors of P450 arom, P450 17, and P450 TxA2

    Arch. Pharm. Weinh.

    (1996)
    Q. Hu et al.

    Isopropylidene substitution increases activity and selectivity of biphenyl methylene 4-pyridine type CYP17 inhibitors

    J. Med. Chem.

    (2010)
  • Cited by (20)

    • In silico selectivity modeling of pyridine and pyrimidine based CYP11B1 and CYP11B2 inhibitors: A case study

      2022, Journal of Molecular Graphics and Modelling
      Citation Excerpt :

      This indeed directed the scientists to develop selective drugs for both targets for the treatment of different disease conditions. If CYP11B2 is targeted with non-selective drugs it may also inhibit the CYP11B1 and decreases the level of glucocorticoids and may cause severe side effect, which ultimately leads to the progress of an addisonian crisis, cardiovascular collapse, and death [26,27]. CYP11B2 inhibitor in a clinical trial also showed selectivity towards CYP11B1 [28].

    • Synthesis, structure, optical and thermal analysis of the new compound of the new compound organo-metallic (C<inf>5</inf>H<inf>6</inf>N)<inf>2</inf>TeCl<inf>6</inf>

      2022, Journal of Molecular Structure
      Citation Excerpt :

      Pyridine is widely used in coordination chemistry as a ligand, and in organic chemistry as a reagent. For instance, pyridine derivatives are frequently used in pharmaceutical compounds [12,13], in biological products [14] and in agrochemistry [15–18]. Pyridine is used as a precursor in the manufacture of insecticides [15], herbicides [17], medicines [14] and food flavorings [15,17].

    View all citing articles on Scopus
    View full text