Saarbrucken, Germany
Saarbrucken, Germany

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Spadaro A.,Saarland University | Spadaro A.,ElexoPharm GmbH | Frotscher M.,Saarland University | Hartmann R.W.,Saarland University | Hartmann R.W.,Helmholtz Institute for Pharmaceutical Research Saarland HIPS
Journal of Medicinal Chemistry | Year: 2012

17β-HSD1 is a novel target for the treatment of estrogen-dependent diseases, as it catalyzes intracellular estradiol formation. Starting from two recently described compounds, highly active and selective inhibitors were developed. Benzoyl 6 and benzamide 17 are the most selective compounds toward 17β-HSD2 described so far. They also showed a promising profile regarding activity in T47-D cells, selectivity toward ERα and ERβ, inhibition of hepatic CYP enzymes, metabolic stability, and inhibition of marmoset 17β-HSD1 and 17β-HSD2. © 2012 American Chemical Society.


Zhu W.,Saarland University | Hu Q.,Saarland University | Hanke N.,ElexoPharm GmbH | Van Koppen C.J.,ElexoPharm GmbH | Hartmann R.W.,Saarland University
Journal of Medicinal Chemistry | Year: 2014

Topical application of CYP11B1 inhibitors to reduce cutaneous cortisol is a novel strategy to promote healing of chronic wounds. Pyridyl substituted arylsulfonyltetrahydroquinolines were designed and synthesized resulting in a strong inhibitor 34 (IC50= 5 nM). It showed no inhibition of CYP17 and CYP19 and no mutagenic effects. It exhibited inverse metabolic stability in plasma (t1/2蠑 150 min), which is similar to wound fluid in composition, and in liver S9 fractions (t1/2= 16 min). © 2014 American Chemical Society.


Yin L.,Saarland University | Yin L.,ElexoPharm GmbH | Hu Q.,Saarland University | Hartmann R.W.,Saarland University
PLoS ONE | Year: 2012

Aldosterone synthase (CYP11B2) is a promising therapeutic target for the treatment of cardiovascular diseases related to abnormally high aldosterone levels. On the basis of our previously identified lead compounds I-III, a series of 3-pyridinyl substituted aliphatic cycles were designed, synthesized and tested as CYP11B2 inhibitors. Aromaticity abolishment of the core was successfully applied to overcome the undesired CYP1A2 inhibition. This study resulted in a series of potent and selective CYP11B2 inhibitors, with compound 12 (IC50 = 21 nM, SF = 50) as the most promising one, which shows no inhibition toward CYP1A2 at 2 μM. The design conception demonstrated in this study can be helpful in the optimization of CYP inhibitor drugs regarding CYP1A2 selectivity. © 2012 Yin et al.


Yin L.,Saarland University | Yin L.,ElexoPharm GmbH | Hu Q.,Saarland University | Hartmann R.W.,Saarland University
Journal of Medicinal Chemistry | Year: 2013

The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3, 2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that is, a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compounds 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound 3p, which exhibited IC50 values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo. © 2013 American Chemical Society.


Emmerich J.,Saarland University | Hu Q.,Saarland University | Hanke N.,ElexoPharm GmbH | Hartmann R.W.,Saarland University
Journal of Medicinal Chemistry | Year: 2013

Potent and selective CYP11B1 inhibitors could be promising therapeutics for the treatment of Cushing's syndrome. Optimization of Ref 1 (5-((1H-imidazol-1- yl)methyl)-2-phenylpyridine) led to compound 44 (5-((5-methylpyridin-3-yl) methyl)-2-phenylpyridine) with a 50-fold improved IC50 value of 2 nM toward human CYP11B1 and an enhanced inhibition of the rat enzyme (IC 50 = 2440 nM) compared to Ref 1 (IC50 > 10000 nM). Furthermore, selectivities over CYP11B2, CYP17, and CYP19 were observed, as well as satisfying metabolic stability not only in human and rat plasma but also in liver S9 fraction. Investigation of cytotoxicity and inhibition of hepatic CYP2A6 and CYP3A4 showed that 44 fulfills first safety criteria and can be considered for further in vivo evaluation in rats. © 2013 American Chemical Society.


Van Koppen C.J.,ElexoPharm GmbH | Hartmann R.W.,ElexoPharm GmbH | Hartmann R.W.,Saarland University | Hartmann R.W.,Helmholtz Institute for Pharmaceutical Research Saarland
Expert Opinion on Therapeutic Patents | Year: 2015

Introduction: About 2% of the Western world population suffer from chronic wounds, resulting from underlying disorders (e.g., diabetes, excessive pressure, vascular insufficiencies and vasculitis), with a significant adverse effect on Quality of Life. Despite high incidence and economic burden, management of chronic wounds is still far from effective and novel therapies are in urgent need. Wound healing is a dynamic process of transient expression, function and clearance of mediators, enzymes and cell types. Failure to initiate, terminate or regulate leads to pathologic wound healing.Areas covered: The present review discusses patents of the seven most promising classes of biological agents, mostly published in 2009-2014 (CYP11B1 inhibitors, peptide growth factors, prolyl-4-hydroxylase and matrix metalloproteinase inhibitors, bone marrow-derived mesenchymal stem cells, elastase and connexin43 inhibitors). Relevant information from peer-reviewed journals is also presented.Expert Opinion: The aforementioned biological agents have different mechanisms of action, and considering the multifactorial pathogenesis of chronic wounds, they hold promise in treating chronic wounds. However, as administration of a certain biological agent may be beneficial in an early phase, it may slow down wound healing in a later phase. Basic and clinical research on chronic wound healing should therefore investigate the efficacy of these agents, alone and in concert, during the consecutive phases of wound healing. © Informa UK, Ltd.


Patent
ElexoPharm GmbH and Sharp Corporation | Date: 2013-10-02

This invention relates to indo line compounds of the structural formula I, or their pharmaceutically acceptable salts, wherein the variables are defined herein. The inventive compounds selectively inhibit aldosterone synthase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as potentially to methods for the treatment amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthase.


Patent
Sharp Corporation and ElexoPharm GmbH | Date: 2016-06-30

This invention relates to indoline compounds of the structural formula: or their pharmaceutically acceptable salts, wherein the variables are defined herein. The inventive compounds selectively inhibit aldosterone synthase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as potentially to methods for the treatment, amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthase.


Patent
ElexoPharm GmbH and Schering | Date: 2012-04-20

This invention relates to tricyclic triazole analogues of the formula I or their pharmaceutically acceptable salts, wherein the variable are defined herein. The inventive compounds selectively inhibit aldosterone synthetase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as to methods for the treatment, amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthetase.


Provided herein are non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 and type 2 (17-HSD1 and 17-HSD2) inhibitors, their production and use, especially for the treatment and for prophylaxis of hormone-related diseases.

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