Original article1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors
Graphical abstract
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 1–4 (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.
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