Rolf W Hartmann

Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Saarland, Germany

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Publications (319)929.84 Total impact

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    ABSTRACT: Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration). Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 01/2015; 89:106–114. · 3.43 Impact Factor
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    ABSTRACT: 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.
    European Journal of Medicinal Chemistry 01/2015; 89. · 3.43 Impact Factor
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    ABSTRACT: Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 μM). Copyright © 2014. Published by Elsevier Masson SAS.
    European Journal of Medicinal Chemistry 12/2014; 90C:788-796. · 3.43 Impact Factor
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    ABSTRACT: In order to identify new scaffolds for drug discovery, surface plasmon resonance is frequently used to screen structurally diverse libraries. Usually, hit rates are low and identification processes are time consuming. Hence, approaches which improve hit rates and, thus, reduce the library size are required. In this work, we studied three often used strategies for their applicability to identify inhibitors of PqsD. In two of them, target-specific aspects like inhibition of a homologous protein or predicted binding determined by virtual screening were used for compound preselection. Finally, a fragment library, covering a large chemical space, was screened and served as comparison. Indeed, higher hit rates were observed for methods employing preselected libraries indicating that target-oriented compound selection provides a time-effective alternative.
    Future medicinal chemistry 12/2014; 6(18):2057-72. · 4.00 Impact Factor
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    ABSTRACT: A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo. Copyright © 2014. Published by Elsevier Masson SAS.
    European Journal of Medicinal Chemistry 11/2014; 90C:351-359. · 3.43 Impact Factor
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  • ChemInform 11/2014; 45(45).
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    ABSTRACT: In Alzheimer's disease (AD), multiple factors account for the accumulation of neurocellular changes, which may begin several years before symptoms appear. The most important pathogenic brain changes that are contributing to the development of AD are the formation of the cytotoxic β-amyloid aggregates and of the neurofibrillary tangles, which originate from amyloid-β peptides and hyperphosphorylated tau protein, respectively. New therapeutic agents that target both major pathogenic mechanisms may be particularly efficient. In this study, we introduce bis(hydroxyphenyl)-substituted thiophenes as a novel class of selective, dual inhibitors of the tau kinase Dyrk1A and of the amyloid-β aggregation.
    ACS Chemical Neuroscience 09/2014; · 4.21 Impact Factor
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    ABSTRACT: 17β-HSD2 is a promising new target for the treatment of osteoporosis. In this paper, a rational strategy to overcome the metabolic liability in the 2,5-thiophene amide class of 17β-HSD2 inhibitors is described, and the biological activity of the new inhibitors. Applying different strategies, as lowering the cLogP or modifying the structures of the molecules, compounds 27, 31 and 35 with strongly improved metabolic stability were obtained. For understanding biotransformation in the 2,5-thiophene amide class the main metabolic pathways of three properly selected compounds were elucidated.
    European Journal of Medicinal Chemistry 09/2014; 87:203-219. · 3.43 Impact Factor
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    ABSTRACT: Dysregulated usage of pre-mRNA splicing sites contributes to the progression of cancer, neurodegenerative diseases, and viral infections. Serine/arginine-rich (SR) proteins play major roles in the splice site recognition and are largely regulated by phosphorylation. This provides an option for the pharmacological correction of aberrant splicing by inhibiting the relevant kinases. Cdc2-like kinases (Clks) and dual specificity tyrosine phosphorylation-regulated kinases (Dyrks) were both reported to phosphorylate numerous SR proteins in vitro and in vivo. In this study, we describe the discovery of new selective dual Clk/Dyrk1A/1B inhibitors, which are able to modulate alternative pre-mRNA splicing of model gene transcripts in cells with submicromolar potencies. The optimization process yielded a dual Clk and Dyrk inhibitor with exceptionally high ligand efficiency. Our results suggested that dual inhibition of both Clk1 and Dyrk1A increased the efficacy of pre-mRNA splicing modulation.
    ACS Medicinal Chemistry Letters 09/2014; 5(9):963-7. · 3.07 Impact Factor
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    ABSTRACT: The bacterial RNA polymerase (RNAP) represents a validated target for the development of broad-spectrum antibiotics. However, the medical value of RNAP inhibitors in clinical use is limited by the prevalence of resistant strains. To overcome this problem, we focused on the exploration of alternative target sites within the RNAP. Previously, we described the discovery of a novel RNAP inhibitor class containing an ureidothiophene-2-carboxylic acid core structure. Herein, we demonstrate that these compounds are potent against a set of methicillin-resistant Staphylococcus aureus (MRSA) strains (MIC: 2-16 μg ml-1) and rifampicin-resistant Escherichia coli TolC strains (MIC: 12.5-50 μg ml-1). Additionally, an abortive transcription assay revealed that these compounds inhibit the bacterial transcription process during the initiation phase. Furthermore, the binding mode of the ureidothiophene-2-carboxylic acids was characterized by mutagenesis studies and ligand-based NMR spectroscopy. Competition saturation transfer difference (STD) NMR experiments with the described RNAP inhibitor myxopyronin A (Myx) suggest that the ureidothiophene-2-carboxylic acids compete with Myx for the same binding site in the RNAP switch region. INPHARMA (Interligand NOE for PHARmacophore MApping) experiments and molecular docking simulations provided a binding model in which the ureidothiophene-2-carboxylic acids occupy the region of the Myx western chain binding site and slightly occlude that of the eastern chain. These results demonstrate that the ureidothiophene-2-carboxylic acids are a highly attractive new class of RNAP inhibitors that can avoid the problem of resistance.
    ACS Chemical Biology 09/2014; · 5.36 Impact Factor
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    ABSTRACT: Antibiotic resistance has become a major health problem. The σ(70):core interface of bacterial RNA polymerase is a promising drug target. Recently, the coiled-coil and lid-rudder-system of the β' subunit has been identified as an inhibition hot spot. Materials & methods & Results: By using surface plasmon resonance-based assays, inhibitors of the protein-protein interaction were identified and competition with σ(70) was shown. Effective inhibition was verified in an in vitro transcription and a σ(70):core assembly assay. For one hit series, we found a correlation between activity and affinity. Mutant interaction studies suggest the inhibitors' binding site.
    Future medicinal chemistry 09/2014; 6(14):1551-65. · 4.00 Impact Factor
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    ABSTRACT: A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5-aryl-1,3,4-thiadiazol-2-yl)-imino-pregnenolone derivatives 11–15 were more active than the sulfonate 24–31 and the ester 37–41 analogs. Derivative 12 showed optimal activity in this series, with IC50 values of 2.5 µM compared with the standard abiraterone (IC50 = 0.07 µM). However, the analogs 11 and 25 showed a better selectivity profile (81.5 and 82.7% inhibition of hydroxylase, respectively), which may be a useful lead in CYP17 inhibition studies. Molecular docking studies demonstrated quite similar binding patterns of all new pregnenolone derivatives at the active site of CYP17 through hydrogen bonding and hydrophobic interaction.
    Archiv der Pharmazie 09/2014; · 1.54 Impact Factor
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    ABSTRACT: 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 > 150 min), which is similar to wound fluid in composition, and in liver S9 fractions (t1/2 = 16 min).
    Journal of Medicinal Chemistry 08/2014; · 5.48 Impact Factor
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    ABSTRACT: FULL PAPER Martin Empting, Rolf W. Hartmann et al. From in vitro to in cellulo: structure–activity relationship of (2-nitrophenyl)- methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa
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    ABSTRACT: There is increasing evidence that the atypical protein kinase C, PKCζ, might be a therapeutic target in pulmonary and hepatic inflammatory diseases. However, targeting the highly conserved ATP-binding pocket in the catalytic domain held little promise to achieve selective inhibition. In the present study, we introduce 1,3,5-trisubstituted pyrazolines as potent and selective allosteric PKCζ inhibitors. The rigid scaffold offered many sites for modification, all acting as hot spots for improving activity, and gave rise to sharp structure-activity relationships. Targeting of PKCζ in cells was confirmed by reporter gene assay, transfection assays, and Western blotting. The strongly reduced cell-free and cellular activities toward a PIF-pocket mutant of PKCζ suggested that the inhibitors most likely bound to the PIF-pocket on the kinase catalytic domain. Thus, using a rigidification strategy and by establishing and optimizing multiple molecular interactions with the binding site, we were able to significantly improve the potency of the previously reported PKCζ inhibitors.
    Journal of Medicinal Chemistry 07/2014; · 5.48 Impact Factor
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    ABSTRACT: The inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes the conversion of estrone into the potent estrogen receptor agonist estradiol (E2), is discussed as a novel therapeutic approach for the treatment of estrogen-dependent diseases. Because the reduction of E2 would be basically limited to the target tissues, this approach is expected to cause fewer side effects than the currently employed antihormonal therapies. Recently, we reported on 6-hydroxybenzothiazole ketones as a new class of 17β-HSD1 inhibitors with a notable activity/selectivity profile. In an attempt to further optimize these parameters, we modified the benzothiazole core by a systematic bioisosteric replacement. Thus, we were able to identify a new 6-hydroxybenzothiophene derivative that displayed stronger inhibition of 17β-HSD1 (IC50=13 nM) and that was also more selective than a benzothiazole analog. Using ab initio calculations, we found that the higher potency of the 6-hydroxybenzothiophene derivative was probably due to more favorable conformational preorganization of the scaffold for binding to the enzyme.
    ChemMedChem 07/2014; · 3.05 Impact Factor
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    ABSTRACT: Cystic fibrosis (CF) is a genetic disease mainly manifested in the respiratory tract. Pseudomonas aeruginosa (P. aeruginosa) is the most common pathogen identified in cultures of the CF airways, however, its eradication with antibiotics remains challenging as it grows in biofilms that counterwork human immune response and dramatically decrease the susceptibility to antibiotics. P. aeruginosa regulates pathogenicity via a cell-to-cell communication system known as quorum sensing (QS) involving the virulence factor (pyocyanin), thus representing an attractive target for coping bacterial pathogenicity. The first in vivo potent QS inhibitor (QSI) was recently developed. Nevertheless, its lipophilic nature might hamper its penetration of non-cellular barriers such as mucus and bacterial biofilms, which limits its biomedical application. Successful anti-infective inhalation therapy necessitates proper design of a biodegradable nanocarrier allowing: 1) High loading and prolonged release, 2) Mucus penetration, 3) Effective pulmonary delivery, and 4) Maintenance of the anti-virulence activity of the QSI. In this context, various pharmaceutical lipids were used to prepare ultra-small solid lipid nanoparticles (us-SLNs) by hot melt homogenization. Plain and QSI-loaded SLNs were characterized in terms of colloidal properties, drug loading, in vitro release and acute toxicity on Calu-3 cells. Mucus penetration was studied using newly-developed confocal microscopy technique based on 3D-time laps imaging. For pulmonary application, nebulization efficiency of SLNs and lung deposition using next generation impactor (NGI) were performed. The anti-virulence efficacy was investigated by pyocyanin formation in P. aeruginosa cultures. Ultra-small SLNs (<100 nm diameter) provided high encapsulation efficiency (68 - 95 %) according to SLNs composition, high burst in phosphate buffer saline compared to prolonged release of the payload over>8 h in simulated lung fluid with minor burst. All types and concentrations of plain and QSI-loaded SLNs maintained the viability of Calu-3 cells. 3D-time laps confocal imaging proved the ability of SLNs to penetrate into artificial sputum model. SLNs were efficiently nebulized; NGI experiments revealed their deposition in the bronchial region. Overall, nanoencapsulated QSI showed up to sevenfold superior anti-virulence activity to the free compound. Most interestingly, the plain SLNs exhibited anti-virulence properties themselves, which was shown to be related to anti-virulence effects of the emulsifiers used. These startling findings represent a new perspective of ultimate significance in the area of the nano-based delivery of novel anti-infectives.
    Journal of Controlled Release 07/2014; · 7.26 Impact Factor
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    ABSTRACT: 17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) is responsible for the oxidation of the highly active estradiol (E2) and testosterone (T) into the less potent estrone (E1) and Δ4-androstene-3,17-dione (Δ4-AD), respectively. As 17β-HSD2 is present in bones and as estradiol and testosterone are able to induce bone formation and repress bone resorption, inhibition of this enzyme could be a new promising approach for the treatment of osteoporosis. Herein, we describe the design, the synthesis and the biological evaluation of 24 new 17β-HSD2 inhibitors in the 5-substituted thiophene-2-carboxamide class. Structure-activity and structure-selectivity relationships have been explored by variation of the sulfur atom position in the central core, exchange of the thiophene by a thiazole, substitution of the amide group with a larger moiety, exchange of the N-methylamide group with bioisosteres like N-methylsulfonamide, N-methylthioamide and ketone, and substitutions at positions 2 and 3 of the thiophene core with alkyl and phenyl groups leading to 2,3,5-trisubstituted thiophene derivatives. The compounds were evaluated on human and mouse enzymes. From this study, a novel highly potent and selective compound in both human and mouse 17β-HSD2 enzymes was identified, compound 21 (IC50(h17β-HSD2) = 235 nM, Selectivity Factor toward h17β-HSD1 = 95, IC50 (m17β-HSD2) = 54 nM). This new compound 21 could be used for an in vivo proof of principle to demonstrate the true therapeutic efficacy of 17β-HSD2 inhibitors in osteoporosis. New structural insights into the active sites of the human and mouse enzymes were gained.
    European Journal of Medicinal Chemistry 06/2014; 83:317-337. · 3.43 Impact Factor
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    ABSTRACT: Recent studies have shown that compounds based on a (2-nitrophenyl)methanol scaffold are promising inhibitors of PqsD, a key enzyme of signal molecule biosynthesis in the cell-to-cell communication of Pseudomonas aeruginosa. The most promising molecule displayed anti-biofilm activity and a tight-binding mode of action. Herein, we report on the convenient synthesis and biochemical evaluation of a comprehensive series of (2-nitrophenyl)methanol derivatives. The in vitro potency of these inhibitors against recombinant PqsD as well as the effect of selected compounds on the production of the signal molecules HHQ and PQS in P. aeruginosa were examined. The gathered data allowed the establishment of a structure-activity relationship, which was used to design fluorescent inhibitors, and finally, led to the discovery of (2-nitrophenyl)methanol derivatives with improved in cellulo efficacy providing new perspectives towards the application of PqsD inhibitors as anti-infectives.
    Organic & Biomolecular Chemistry 06/2014; · 3.49 Impact Factor

Publication Stats

3k Citations
929.84 Total Impact Points


  • 2010–2014
    • Helmholtz Institute for Pharmaceutical Research Saarland
      Saarbrücken, Saarland, Germany
    • University of Vienna
      Wien, Vienna, Austria
  • 1992–2014
    • Universität des Saarlandes
      • Pharmazeutische und Medizinische Chemie
      Saarbrücken, Saarland, Germany
  • 2013
    • The German University in Cairo
      • Department of Pharmaceutical Chemistry
      Cairo, Muhafazat al Qahirah, Egypt
  • 2011–2012
    • The Maharaja Sayajirao University of Baroda
      • Department of Pharmacy
      Vadodara, State of Gujarat, India
  • 2005–2011
    • Università degli Studi di Bari Aldo Moro
      • Dipartimento di Farmacia - Scienze del Farmaco
      Bari, Apulia, Italy
  • 2001–2010
    • University of Bologna
      • Department of Pharmacy and Biotechnology FaBiT
      Bologna, Emilia-Romagna, Italy
  • 1986–2007
    • Universität Regensburg
      • Institut für Pharmazie
      Regensburg, Bavaria, Germany
  • 2003–2006
    • University of Nantes
      Naoned, Pays de la Loire, France
  • 2004–2005
    • Panjab University
      Chandigarh, Chandīgarh, India
    • King Faisal Specialist Hospital and Research Centre
      • Department of Biological and Medical Research
      Jeddah, Mintaqat Makkah, Saudi Arabia
  • 1990
    • Freie Universität Berlin
      • Institute of Pharmacy
      Berlín, Berlin, Germany