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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.


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.


Yin L.,Saarland University | Yin L.,ElexoPharm GmbH | Hu Q.,Saarland University | Emmerich J.,Saarland University | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2014

Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC 50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs < 15). These potent CYP11B2 inhibitors exhibited no inhibition (IC50 > 50 μM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation. © 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.


Hu Q.,Saarland University | Yin L.,Saarland University | Yin L.,ElexoPharm GmbH | Jagusch C.,Saarland University | And 3 more authors.
Journal of Medicinal Chemistry | Year: 2010

CYP17 inhibition is a promising therapy for prostate cancer (PC) because proliferation of 80% of PC depends on androgen stimulation. Introduction of isopropylidene substituents onto the linker of biphenylmethylene 4-pyridines resulted in several strong CYP17 inhibitors, which were more potent and selective, regarding CYP 11B1, 11B2, 19 and 3A4, than the drug candidate abiraterone. © 2010 American Chemical Society.

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