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Anthranilic Acid

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Daniel Merk – One of the best experts on this subject based on the ideXlab platform.

  • Anthranilic Acid derivatives as nuclear receptor modulators development of novel ppar selective and dual ppar fxr ligands
    Bioorganic & Medicinal Chemistry, 2015
    Co-Authors: Daniel Merk, Matthias Gabler, Daniel Flesch, Christina Lamers, Julia Weber, Ewgenij Proschak, Manfred Schubertzsilavecz

    Abstract:

    Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of Anthranilic Acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism.

  • Anthranilic Acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands
    Bioorganic & Medicinal Chemistry, 2014
    Co-Authors: Daniel Merk, Matthias Gabler, Daniel Flesch, Christina Lamers, Julia Weber, Ewgenij Proschak, Manfred Schubert-zsilavecz

    Abstract:

    Abstract Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of Anthranilic Acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism.

  • Anthranilic Acid derivatives as novel ligands for farnesoid x receptor fxr
    Bioorganic & Medicinal Chemistry, 2014
    Co-Authors: Daniel Merk, Matthias Gabler, Roberto Carrasco Gomez, Daniel Flesch, Thomas Hanke, Astrid Kaiser, Christina Lamers, Oliver Werz, Gisbert Schneider

    Abstract:

    Abstract Nuclear farnesoid X receptor (FXR) has important physiological roles in various metabolic pathways including bile Acid, cholesterol and glucose homeostasis. The clinical use of known synthetic non-steroidal FXR ligands is restricted due to toxicity or poor bioavailability. Here we report the development, synthesis, in vitro activity and structure–activity relationship (SAR) of Anthranilic Acid derivatives as novel FXR ligands. Starting from a virtual screening hit we optimized the scaffold to a series of potent partial FXR agonists with appealing drug-like properties. The most potent derivative exhibited an EC50 value of 1.5 ± 0.2 μM and 37 ± 2% maximum relative FXR activation. We investigated its SAR regarding polar interactions with the receptor by generating derivatives and computational docking.

Stanislav Gobec – One of the best experts on this subject based on the ideXlab platform.

  • Anthranilic Acid Inhibitors of Undecaprenyl Pyrophosphate Synthase (UppS), an Essential Enzyme for Bacterial Cell Wall Biosynthesis
    Frontiers in Microbiology, 2018
    Co-Authors: Marko Jukič, Kaja Rožman, Matej Sova, Hélène Barreteau, Stanislav Gobec

    Abstract:

    We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from Escherichia coli. UppS is an essential enzyme in the biosynthesis of bacterial cell wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new cis-double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antibacterial drug design. A pharmacophore model was designed on a known bisphosphonate BPH-629 and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three Anthranilic Acid derivatives with promising inhibitory activity against UppS. Compound 2 displayed high inhibitory potency (IC50 = 25 μM) and good antibacterial activity against E. coli BW25113 ΔtolC strain (MIC = 0.5 μg/mL).

  • n benzoyl Anthranilic Acid derivatives as selective inhibitors of aldo keto reductase akr1c3
    Bioorganic & Medicinal Chemistry Letters, 2012
    Co-Authors: Masa Sinreih, Izidor Sosič, Natasa Beranic, Samo Turk, Adegoke O Adeniji, Trevor M. Penning, Tea Lanišnik Rižner, Stanislav Gobec

    Abstract:

    Abstract Human aldo–keto reductases AKR1C1–AKR1C3 are involved in the biosynthesis and inactivation of steroid hormones and prostaglandins and thus represent attractive targets for the development of new drugs. We synthesized a series of N -benzoyl Anthranilic Acid derivatives and tested their inhibitory activity on AKR1C enzymes. Our data show that these derivatives inhibit AKR1C1–AKR1C3 isoforms with low micromolar potency. In addition, five selective inhibitors of AKR1C3 were identified. The most promising inhibitors were compounds 10 and 13 , with IC 50 values of 0.31 μM and 0.35 μM for AKR1C3, respectively.

  • N-Benzoyl Anthranilic Acid derivatives as selective inhibitors of aldo–keto reductase AKR1C3
    Bioorganic & Medicinal Chemistry Letters, 2012
    Co-Authors: Masa Sinreih, Izidor Sosič, Natasa Beranic, Samo Turk, Adegoke O Adeniji, Trevor M. Penning, Tea Lanišnik Rižner, Stanislav Gobec

    Abstract:

    Abstract Human aldo–keto reductases AKR1C1–AKR1C3 are involved in the biosynthesis and inactivation of steroid hormones and prostaglandins and thus represent attractive targets for the development of new drugs. We synthesized a series of N -benzoyl Anthranilic Acid derivatives and tested their inhibitory activity on AKR1C enzymes. Our data show that these derivatives inhibit AKR1C1–AKR1C3 isoforms with low micromolar potency. In addition, five selective inhibitors of AKR1C3 were identified. The most promising inhibitors were compounds 10 and 13 , with IC 50 values of 0.31 μM and 0.35 μM for AKR1C3, respectively.

Matthias Gabler – One of the best experts on this subject based on the ideXlab platform.

  • Anthranilic Acid derivatives as nuclear receptor modulators development of novel ppar selective and dual ppar fxr ligands
    Bioorganic & Medicinal Chemistry, 2015
    Co-Authors: Daniel Merk, Matthias Gabler, Daniel Flesch, Christina Lamers, Julia Weber, Ewgenij Proschak, Manfred Schubertzsilavecz

    Abstract:

    Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of Anthranilic Acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism.

  • Anthranilic Acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands
    Bioorganic & Medicinal Chemistry, 2014
    Co-Authors: Daniel Merk, Matthias Gabler, Daniel Flesch, Christina Lamers, Julia Weber, Ewgenij Proschak, Manfred Schubert-zsilavecz

    Abstract:

    Abstract Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of Anthranilic Acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism.

  • Anthranilic Acid derivatives as novel ligands for farnesoid x receptor fxr
    Bioorganic & Medicinal Chemistry, 2014
    Co-Authors: Daniel Merk, Matthias Gabler, Roberto Carrasco Gomez, Daniel Flesch, Thomas Hanke, Astrid Kaiser, Christina Lamers, Oliver Werz, Gisbert Schneider

    Abstract:

    Abstract Nuclear farnesoid X receptor (FXR) has important physiological roles in various metabolic pathways including bile Acid, cholesterol and glucose homeostasis. The clinical use of known synthetic non-steroidal FXR ligands is restricted due to toxicity or poor bioavailability. Here we report the development, synthesis, in vitro activity and structure–activity relationship (SAR) of Anthranilic Acid derivatives as novel FXR ligands. Starting from a virtual screening hit we optimized the scaffold to a series of potent partial FXR agonists with appealing drug-like properties. The most potent derivative exhibited an EC50 value of 1.5 ± 0.2 μM and 37 ± 2% maximum relative FXR activation. We investigated its SAR regarding polar interactions with the receptor by generating derivatives and computational docking.