Klaus Griessbach

University of Münster, Muenster, North Rhine-Westphalia, Germany

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Publications (4)8.21 Total impact

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    ABSTRACT: Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is an enzyme, which is induced during the inflammatory response. Therefore, inhibitors of this enzyme are considered to be potential anti-inflammatory drugs. We have identified 3-(4-dodecanoyl-1,3,5-trimethylpyrrol-2-yl)propionic acid (12) as submicromolar inhibitor of mPGES-1. Surprisingly, structural variations made around this lead only resulted in a relatively small change of enzyme inhibitory potency. Such flat structure-activity relationships are reported to be typical for so called nuisance inhibitors, which exert their action not by directly binding to the enzyme, but by forming colloid-like aggregates at micromolar and sometimes submicromolar concentrations, which somehow sequester and inhibit enzyme targets without specificity. Since aggregate-based inhibition is highly sensitive to non-ionic detergents such as Triton X-100, we investigated some of our compounds for inhibition of human recombinant mPGES-1 also in presence of this detergent. The pyrrole derivatives 12, 67 and 81, which exhibited IC(50) values in absence of Triton X-100 in the range of 0.1 and 1μM, were virtually inactive at the highest test concentration of 10μM when 0.1% of the detergent was added. In the same way, the published mPGES-1 inhibitor 2-[(4-{[(1,1'-biphenyl)-4-ylmethyl]amino}-6-chloropyrimidin-2-yl)thio]octanoic acid (Cay10589) (6) totally lost its activity under these conditions. Therefore, these compounds have to be judged as nuisance inhibitors of the enzyme. In contrast, the known indole derivative 3-[3-(tert-butylthio)-1-(4-chlorobenzyl)-5-isopropylindol-2-yl]-2,2-dimethylpropionic acid (MK-886) (2) showed a considerable activity (75% inhibition at 10μM) also in the presence of Triton X-100.
    No preview · Article · Dec 2011 · European Journal of Medicinal Chemistry
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    ABSTRACT: The cell lytic and cytosolic phospholipase A2 (cPLA2)-inhibitory properties of the commercially available fluoroderivatives arachidonyltrifluoromethyl ketone (AACOCF3), methyl arachidonylfluorophosphonate (MAFP) and palmityltrifluoromethyl ketone (PACOCF3) in washed bovine platelets were determined.AACOCF3 and MAFP showed platelet cytotoxicity at 33 μM. At this concentration both compounds led to a liberation of lactate dehydrogenase from the cells. Contrary to the findings with MAFP, AACOCF3 also caused a decrease in the turbidity of the platelet suspension at 33 μM. For PACOCF3 no cytotoxic effects could be measured at 33 μM. While AACOCF3 and MAFP inhibited the cPLA2-mediated arachidonic acid release in calcium ionophore A23187-stimulated platelets to approximately the same extent (IC50: 11 and 7 μM, respectively), PACOCF3 was not active at the highest concentration tested (33 μM).Since AACOCF3 and MAFP showed cytotoxic properties at concentrations close to their IC50 values against cPLA2, care must be taken when using these inhibitors to investigate the role of cPLA2 in the mediation of arachidonic acid release in intact cells.
    No preview · Article · Feb 2010
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    ABSTRACT: A series of 3-dodecanoylindole-2-carboxylic acid derivatives with varied carboxylic acid substituents at the indole 1-position were synthesized and evaluated for their ability to inhibit arachidonic acid release in human platelets mediated by the cytosolic phospholipase A(2). Structure-activity relationship studies revealed that increasing the polarity of these substituents by the introduction of additional polar groups in the proximity of the carboxylic acid moiety reduced activity. Conformational restriction of the indole-1-carboxylic acid substituents in distinct positions as well as extending the length of these residues led to compounds which did not substantially differ in their potencies.
    No preview · Article · Dec 2002 · Archiv der Pharmazie
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    M Lehr · K Griessbach
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    ABSTRACT: The effect of various phospholipase A2 and protein kinase inhibitors on the arachidonic acid liberation in bovine platelets induced by the protein kinase activator 12-O-tetradecanoylphorbol-13-acetate (TPA) was studied. TPA stimulates arachidonic acid release mainly by activating group IV cytosolic PLA2 (cPLA2), since inhibitors of this enzyme markedly inhibited arachidonic acid formation. However, group VI Ca2+-independent PLA2 (iPLA2) seems to contribute to the arachidonic acid liberation too, since the relatively specific iPLA2 inhibitor bromoenol lactone (BEL) decreased arachidonic acid generation in part. The pronounced inhibition of the TPA-induced arachidonic acid release by the protein kinase C (PKC) inhibitors GF 109203X and Ro 31-82220, respectively, and by the p38 MAP kinase inhibitor SB 202190 suggests that the activation of the PLA2s by TPA is mediated via PKC and p38 MAP kinase.
    Preview · Article · Feb 2000 · Mediators of Inflammation

Publication Stats

36 Citations
8.21 Total Impact Points


  • 2002-2011
    • University of Münster
      • Institute of Pharmaceutical and Medicinal Chemistry
      Muenster, North Rhine-Westphalia, Germany
  • 2010
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany