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Manfred Schubert-zsilavecz - One of the best experts on this subject based on the ideXlab platform.
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MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer's disease.
Alzheimer's research & therapy, 2018Co-Authors: Maximilian Pohland, Mario Wurglics, Maren Pellowska, Stephanie Hagl, Heike Asseburg, Martina Reutzel, Aljoscha Joppe, Dirk Berressem, Schamim H. Eckert, Manfred Schubert-zsilaveczAbstract:Current approved drugs for Alzheimer’s disease (AD) only attenuate symptoms, but do not cure the disease. The Pirinixic Acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD. Three-month-old Thy-1 AβPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ1–40 and Aβ1–42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively. MH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence. MH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.
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Substrate-specific effects of Pirinixic Acid derivatives on ABCB1-mediated drug transport
Oncotarget, 2016Co-Authors: Martin Michaelis, Florian Rothweiler, Mario Wurglics, Natália Aniceto, Michaela Dittrich, Heiko Zettl, Michael Wiese, Mark N. Wass, Taravat Ghafourian, Manfred Schubert-zsilaveczAbstract:Pirinixic Acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 Pirinixic Acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, Pirinixic Acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, Pirinixic Acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.
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MH84: A Novel γ-Secretase Modulator/PPARγ Agonist—Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer’s Disease
Neurochemical Research, 2016Co-Authors: Maximilian Pohland, Manfred Schubert-zsilavecz, Mario Wurglics, Maren Pellowska, Stephanie Hagl, Gunter P. EckertAbstract:Developing new therapeutic strategies for Alzheimer’s disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293_APPwt model of AD, characterized by elevated beta amyloid protein levels (Aβ_1–42) and mitochondrial dysfunction. MH84 is a derivate of Pirinixic Acid belonging to a novel class of γ-secretase modulators, which combines γ-secretase modulation with activation of peroxisome proliferator–activator receptor gamma (PPARγ). The mitochondria modifying Dimebon, the γ-secretase blocker DAPT, and the PPARγ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1α indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, Aβ_1–42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular Aβ_1–42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action.
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SAR studies on FXR modulators led to the discovery of the first combined FXR antagonistic/TGR5 agonistic compound
Future medicinal chemistry, 2016Co-Authors: Christina Lamers, Astrid Kaiser, Daniel Merk, Matthias Gabler, Daniel Flesch, Manfred Schubert-zsilaveczAbstract:Background Bile Acids can serve as signaling molecules by activating the nuclear receptor FXR and the G-protein-coupled receptor TGR5 and both bile Acid receptors are prominent experimental drug targets. Results/methodology: In this study we optimized the fatty Acid mimetic compound Pirinixic Acid to a new scaffold with the aim to develop novel FXR modulatory compounds. After a multistep structure-activity optimization process, we discovered FXR agonistic compounds and the first dual FXR antagonistic and TGR5 agonistic compound 79a. Conclusion With this novel dual activity profile on both bile Acid receptors 79a might be a valuable pharmalogical tool to further study the bile Acid signaling network.
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MH84: A Novel γ-Secretase Modulator/PPARγ Agonist--Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer's Disease.
Neurochemical research, 2015Co-Authors: Maximilian Pohland, Manfred Schubert-zsilavecz, Mario Wurglics, Maren Pellowska, Stephanie Hagl, Gunter P. EckertAbstract:Developing new therapeutic strategies for Alzheimer's disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293APPwt model of AD, characterized by elevated beta amyloid protein levels (Aβ1-42) and mitochondrial dysfunction. MH84 is a derivate of Pirinixic Acid belonging to a novel class of γ-secretase modulators, which combines γ-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARγ). The mitochondria modifying Dimebon, the γ-secretase blocker DAPT, and the PPARγ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1α indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, Aβ1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular Aβ1-42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action.
Oliver Werz - One of the best experts on this subject based on the ideXlab platform.
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Pirinixic Acids: flexible fatty Acid mimetics with various biological activities.
Future medicinal chemistry, 2015Co-Authors: Daniel Merk, Dieter Steinhilber, Oliver Werz, Martina Zettl, Manfred Schubert-zsilaveczAbstract:Pirinixic Acid is a typical fatty Acid mimetic and was developed as synthetic antihyperlipidemic agent. While its target remained unknown in the early development, it has later been characterized as dual PPARα/γ agonist. Based on this activity, Pirinixic Acid has served as a lead compound for several structure-activity relationship (SAR) studies addressing diverse targets for lipid mimetics. Many structural variants of Pirinixic Acid descendants have been developed and thereby potent agents on metabolic, inflammatory and neuroprotective targets were discovered of which some have proven in vivo efficacy. This article reviews Pirinixic Acid descendants along with their in vitro-pharmacological profiles, summarizes their in vivo data and finally gives a future perspective for this valuable class of fatty Acid mimetics.
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identification of Pirinixic Acid derivatives bearing a 2 aminothiazole moiety combines dual pparα γ activation and dual 5 lo mpges 1 inhibition
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Thomas Hanke, Oliver Werz, Gisbert Schneider, Christina Lamers, Roberto Carrasco Gomez, Manfred SchubertzsilaveczAbstract:Abstract The concept of dual PPARα/γ activation was originally proposed as a new approach for the treatment of the metabolic syndrome. However, recent results indicated that PPARα as well as PPARγ activation might also be beneficial in the treatment of inflammatory diseases and cancer. We have recently identified aminothiazole-featured Pirinixic Acids as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors. Here we present the structure–activity relationship of these aminothiazole-featured Pirinixic Acids as dual PPARα/γ agonists and discuss their advantages with their potential as dual 5-LO/mPGES-1 inhibitors in inflammatory and cancer diseases. Various Pirinixic Acid derivatives had already been identified as dual PPARα/γ agonists. However, within this series of aminothiazole-featured Pirinixic Acids we were able to identify the most potent selective PPARγ agonistic Pirinixic Acid derivative (compound 13, (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic Acid)). Therefore, docking of 13 on PPARγ was performed to determine the potential binding mode.
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Identification of Pirinixic Acid derivatives bearing a 2-aminothiazole moiety combines dual PPARα/γ activation and dual 5-LO/mPGES-1 inhibition
Bioorganic & medicinal chemistry letters, 2014Co-Authors: Thomas Hanke, Oliver Werz, Gisbert Schneider, Christina Lamers, Roberto Carrasco Gomez, Manfred Schubert-zsilaveczAbstract:Abstract The concept of dual PPARα/γ activation was originally proposed as a new approach for the treatment of the metabolic syndrome. However, recent results indicated that PPARα as well as PPARγ activation might also be beneficial in the treatment of inflammatory diseases and cancer. We have recently identified aminothiazole-featured Pirinixic Acids as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors. Here we present the structure–activity relationship of these aminothiazole-featured Pirinixic Acids as dual PPARα/γ agonists and discuss their advantages with their potential as dual 5-LO/mPGES-1 inhibitors in inflammatory and cancer diseases. Various Pirinixic Acid derivatives had already been identified as dual PPARα/γ agonists. However, within this series of aminothiazole-featured Pirinixic Acids we were able to identify the most potent selective PPARγ agonistic Pirinixic Acid derivative (compound 13, (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic Acid)). Therefore, docking of 13 on PPARγ was performed to determine the potential binding mode.
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A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl Pirinixic Acid scaffold.
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Martina Hieke, Manfred Schubert-zsilavecz, Christine Greiner, Oliver Werz, Theresa M. Thieme, Heiko ZettlAbstract:Abstract Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic Acid cascade. Herein, a class of α-naphthyl Pirinixic Acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC50 mPGES-1 = 0.94 μM; IC50 5-LO = 0.1 μM) showing the most favorable in vitro pharmacological profile.
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Interference of alpha-alkyl-substituted Pirinixic Acid derivatives with neutrophil functions and signalling pathways.
European journal of pharmacology, 2009Co-Authors: Daniel Poeckel, Laura Popescu, Oliver Rau, Manfred Schubert-zsilavecz, Christine Greiner, Carlo Pergola, Arne Henkel, Oliver WerzAbstract:Pirinixic Acid (Wy-14,643) is an agonist of the peroxisome proliferator-activated receptor (PPAR) subtype alpha exhibiting beneficial effects in various inflammation-related processes in a slow, long-termed fashion. We recently showed that alpha-substituted Pirinixic Acid derivatives are agonists of PPAR alpha and act as dual inhibitors of 5-lipoxygenase (5-LO, EC 1.13.11.34) and the microsomal prostaglandin E(2) synthase-1 (EC 5.3.99.3). Here, we explored short-term effects of alpha-substituted Pirinixic Acid derivatives on typical neutrophil functions evoked by the agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP) including leukotriene formation, generation of reactive oxygen species, and release of human leukocyte elastase (EC 3.4.21.37), and we investigated the modulation of related signalling pathways. Pirinixic Acid derivatives that are substituted with alkyl residues in alpha-position of the carboxylic group and with a 6-aminoquinoline residue at the pyrimidine moiety cause inhibition of leukotriene formation, reactive oxygen species formation, and leukocyte elastase release in response to fMLP. In parallel, Ca(2+) mobilisation and the phosphorylation (activation) of p38 mitogen-activated protein kinase was significantly reduced, whereas phosphorylation of the extracellular signal-regulated kinase-2 was unaffected. Pirinixic Acid itself was not or only marginally active in all these assays. Conclusively, targeted structural modification of Pirinixic Acid leads to bioactive compounds that display immediate anti-inflammatory properties in human neutrophils with potential therapeutic value.
Christine Greiner - One of the best experts on this subject based on the ideXlab platform.
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A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl Pirinixic Acid scaffold.
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Martina Hieke, Manfred Schubert-zsilavecz, Christine Greiner, Oliver Werz, Theresa M. Thieme, Heiko ZettlAbstract:Abstract Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic Acid cascade. Herein, a class of α-naphthyl Pirinixic Acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC50 mPGES-1 = 0.94 μM; IC50 5-LO = 0.1 μM) showing the most favorable in vitro pharmacological profile.
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the molecular pharmacology and in vivo activity of 2 4 chloro 6 2 3 dimethylphenylamino pyrimidin 2 ylthio octanoic Acid ys121 a dual inhibitor of microsomal prostaglandin e2 synthase 1 and 5 lipoxygenase
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Andreas Koeberle, Christine Greiner, Carlo Pergola, Heiko Zettl, Christina Hoernig, Friederike Dehm, Antonietta Rossi, Julia Bauer, Sina Reckel, Hinnak NorthoffAbstract:The microsomal prostaglandin E2 synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E2 biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of Pirinixic Acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of α-( n -hexyl)-substituted Pirinixic Acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic Acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC50 = 3.4 μM), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 ( K D = 10–14 μM). In lipopolysaccharide-stimulated human whole blood, PGE2 formation was concentration dependently inhibited (IC50 = 2 μM), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B2 and 6-keto PGF1α and the COX-1-derived 12( S )-hydroxy-5- cis -8,10- trans -heptadecatrienoic Acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE2 and leukotriene B4 but also of 6-keto PGF1α. Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo.
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Interference of alpha-alkyl-substituted Pirinixic Acid derivatives with neutrophil functions and signalling pathways.
European journal of pharmacology, 2009Co-Authors: Daniel Poeckel, Laura Popescu, Oliver Rau, Manfred Schubert-zsilavecz, Christine Greiner, Carlo Pergola, Arne Henkel, Oliver WerzAbstract:Pirinixic Acid (Wy-14,643) is an agonist of the peroxisome proliferator-activated receptor (PPAR) subtype alpha exhibiting beneficial effects in various inflammation-related processes in a slow, long-termed fashion. We recently showed that alpha-substituted Pirinixic Acid derivatives are agonists of PPAR alpha and act as dual inhibitors of 5-lipoxygenase (5-LO, EC 1.13.11.34) and the microsomal prostaglandin E(2) synthase-1 (EC 5.3.99.3). Here, we explored short-term effects of alpha-substituted Pirinixic Acid derivatives on typical neutrophil functions evoked by the agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP) including leukotriene formation, generation of reactive oxygen species, and release of human leukocyte elastase (EC 3.4.21.37), and we investigated the modulation of related signalling pathways. Pirinixic Acid derivatives that are substituted with alkyl residues in alpha-position of the carboxylic group and with a 6-aminoquinoline residue at the pyrimidine moiety cause inhibition of leukotriene formation, reactive oxygen species formation, and leukocyte elastase release in response to fMLP. In parallel, Ca(2+) mobilisation and the phosphorylation (activation) of p38 mitogen-activated protein kinase was significantly reduced, whereas phosphorylation of the extracellular signal-regulated kinase-2 was unaffected. Pirinixic Acid itself was not or only marginally active in all these assays. Conclusively, targeted structural modification of Pirinixic Acid leads to bioactive compounds that display immediate anti-inflammatory properties in human neutrophils with potential therapeutic value.
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Interference of α-alkyl-substituted Pirinixic Acid derivatives with neutrophil functions and signalling pathways
European Journal of Pharmacology, 2009Co-Authors: Daniel Poeckel, Laura Popescu, Oliver Rau, Manfred Schubert-zsilavecz, Christine Greiner, Carlo Pergola, Arne Henkel, Oliver WerzAbstract:Pirinixic Acid (Wy-14,643) is an agonist of the peroxisome proliferator-activated receptor (PPAR) subtype alpha exhibiting beneficial effects in various inflammation-related processes in a slow, long-termed fashion. We recently showed that alpha-substituted Pirinixic Acid derivatives are agonists of PPAR alpha and act as dual inhibitors of 5-lipoxygenase (5-LO, EC 1.13.11.34) and the microsomal prostaglandin E(2) synthase-1 (EC 5.3.99.3). Here, we explored short-term effects of alpha-substituted Pirinixic Acid derivatives on typical neutrophil functions evoked by the agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP) including leukotriene formation, generation of reactive oxygen species, and release of human leukocyte elastase (EC 3.4.21.37), and we investigated the modulation of related signalling pathways. Pirinixic Acid derivatives that are substituted with alkyl residues in alpha-position of the carboxylic group and with a 6-aminoquinoline residue at the pyrimidine moiety cause inhibition of leukotriene formation, reactive oxygen species formation, and leukocyte elastase release in response to fMLP. In parallel, Ca(2+) mobilisation and the phosphorylation (activation) of p38 mitogen-activated protein kinase was significantly reduced, whereas phosphorylation of the extracellular signal-regulated kinase-2 was unaffected. Pirinixic Acid itself was not or only marginally active in all these assays. Conclusively, targeted structural modification of Pirinixic Acid leads to bioactive compounds that display immediate anti-inflammatory properties in human neutrophils with potential therapeutic value.
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Pirinixic Acid derivatives as novel dual inhibitors of microsomal prostaglandin e2 synthase 1 and 5 lipoxygenase
Journal of Medicinal Chemistry, 2008Co-Authors: Andreas Koeberle, Manfred Schubertzsilavecz, Christine Greiner, Mario Wurglics, Heiko Zettl, Oliver WerzAbstract:Dual inhibition of the prostaglandin (PG) and leukotriene (LT) biosynthetic pathway is supposed to be superior over single interference, both in terms of efficacy and side effects. Here, we present a novel class of dual microsomal PGE2 synthase-1/5-lipoxygenase (5-LO) inhibitors based on the structure of Pirinixic Acid [PA, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic Acid, compound 1]. Target-oriented structural modification of 1, particularly α substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2,3-dimethylaniline by a biphenyl-4-yl-methane-amino residue, resulted in potent suppression of mPGES-1 and 5-LO activity, exemplified by 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic Acid (7b, IC50 = 1.3 and 1 μM, respectively). Select compounds also potently reduced PGE2 and 5-LO product formation in intact cells. Importantly, inhibition of cyclooxygenases-1/2 was significantly less pronounced. Taken together, these pirinixi...
Heiko Zettl - One of the best experts on this subject based on the ideXlab platform.
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Substrate-specific effects of Pirinixic Acid derivatives on ABCB1-mediated drug transport
Oncotarget, 2016Co-Authors: Martin Michaelis, Florian Rothweiler, Mario Wurglics, Natália Aniceto, Michaela Dittrich, Heiko Zettl, Michael Wiese, Mark N. Wass, Taravat Ghafourian, Manfred Schubert-zsilaveczAbstract:Pirinixic Acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 Pirinixic Acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, Pirinixic Acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, Pirinixic Acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.
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A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl Pirinixic Acid scaffold.
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Martina Hieke, Manfred Schubert-zsilavecz, Christine Greiner, Oliver Werz, Theresa M. Thieme, Heiko ZettlAbstract:Abstract Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic Acid cascade. Herein, a class of α-naphthyl Pirinixic Acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC50 mPGES-1 = 0.94 μM; IC50 5-LO = 0.1 μM) showing the most favorable in vitro pharmacological profile.
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Functionalization of fatty Acid mimetics for solid-phase coupling and subsequent target identification.
Archiv der Pharmazie, 2010Co-Authors: Michaela Dittrich, Heiko Zettl, Manfred Schubert-zsilaveczAbstract:Fatty Acid mimetics such as Pirinixic Acid (PA) derivatives and 2-(phenylthio)alkanoic Acid derivatives are drug-like small molecules with an interesting pharmacological profile. Previously, we have characterized PA derivatives (e.g., 1) as dual agonists of peroxisome proliferator-activated receptors (PPARs) α and γ and as inhibitors of microsomal prostaglandin E(2)-synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO). 2-(Phenylthio)alkanoic Acids (e.g., 2) were shown to act as highly active and selective PPARα agonists. Encouraged by these results, we would like to identify other target proteins and, thereby, further explore the pharmacological profile of these molecules. An elegant method to screen for potential interaction partners is the so-called "protein-fishing" approach. Requirement is coupling of a functionalized small molecule to a solid phase which is used for biological experiments. Ideally, the pharmacophore of the small molecule remains intact as far as possible. Here, we describe the successful design and synthesis of functionalized fatty Acid mimetics, thus providing an eligible starting point for solid-phase coupling and subsequent "protein-fishing" experiments.
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the molecular pharmacology and in vivo activity of 2 4 chloro 6 2 3 dimethylphenylamino pyrimidin 2 ylthio octanoic Acid ys121 a dual inhibitor of microsomal prostaglandin e2 synthase 1 and 5 lipoxygenase
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Andreas Koeberle, Christine Greiner, Carlo Pergola, Heiko Zettl, Christina Hoernig, Friederike Dehm, Antonietta Rossi, Julia Bauer, Sina Reckel, Hinnak NorthoffAbstract:The microsomal prostaglandin E2 synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E2 biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of Pirinixic Acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of α-( n -hexyl)-substituted Pirinixic Acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic Acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC50 = 3.4 μM), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 ( K D = 10–14 μM). In lipopolysaccharide-stimulated human whole blood, PGE2 formation was concentration dependently inhibited (IC50 = 2 μM), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B2 and 6-keto PGF1α and the COX-1-derived 12( S )-hydroxy-5- cis -8,10- trans -heptadecatrienoic Acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE2 and leukotriene B4 but also of 6-keto PGF1α. Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo.
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Enantiomer separation and indirect chromatographic absolute configuration prediction of chiral Pirinixic Acid derivatives: Limitations of polysaccharide-type chiral stationary phases in comparison to chiral anion-exchangers.
Journal of chromatography. A, 2009Co-Authors: Michael Lämmerhofer, Manfred Schubert-zsilavecz, Michaela Dittrich, Heiko Zettl, Reinhard Pell, Marek Mahut, Martin Richter, Simone Schiesel, Wolfgang LindnerAbstract:Chiral alpha-arylthiocarboxylic Acids with different substitution patterns, representing new Pirinixic Acid derivatives with dual PPARalpha/gamma agonistic activities, have been separated into enantiomers on tert-butylcarbamoylquinine and quinidine based chiral anion-exchangers and amylose tris(3,5-dimethylphenylcarbamate) coated silica on analytical and preparative scale. Absolute configurations of individual enantiomers were assigned chromatographically via elution orders on the chiral anion-exchangers and were confirmed by stereoselective syntheses via Ewans auxiliaries that have lead to enantiomeric products with known absolute configurations. The results of both methods were in full agreement. Moreover, the receptor stereoselectivity in PPARalpha transactivation activities was consistent within the test set of structurally related compounds. Limited correlation (between elution order and substitution) was observed within the set of alpha-arylthiocarboxylic Acids on the amylose tris(3,5-dimethylphenylcarbamate) based chiral stationary phase (CSP), in particular the elution order changed with remote substitution. This clearly demonstrates the risks of chromatographic absolute configuration assignments by prediction from one structural analog to another one, especially with CSPs such as polysaccharide CSPs that are recognized for their broad applicability due to multiple binding and chiral recognition modes. It is therefore of utmost importance that such chromatographic absolute configuration predictions by extrapolation to structural analogs are combined with orthogonal methods for verification of the results.
Laura Popescu - One of the best experts on this subject based on the ideXlab platform.
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A Pirinixic Acid derivative (LP105) inhibits murine 5-lipoxygenase activity and attenuates vascular remodelling in a murine model of aortic aneurysm
British journal of pharmacology, 2011Co-Authors: M Revermann, Laura Popescu, Mario Wurglics, Ramona Steri, Alexander Paulke, Anja Mieth, Maren Pellowska, Ariane Fischer, Thorsten J. Maier, Ralph T. SchermulyAbstract:BACKGROUND AND PURPOSE Arachidonic Acid derivatives play a central role in inflammation processes. Arachidonic Acid is metabolized by several enzymes, particularly cyclooxygenases (COX), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E-synthase-1 (mPGES-1) to pro-inflammatory mediators. EXPERIMENTAL APPROACH We determined the effect of LP105, a Pirinixic Acid derivative which acts as inhibitor of 5-LOX, COX and mPGES-1, on aortic aneurysm development in mice and on 5-LOX activity in murine monocytes. KEY RESULTS In a monocyte cell line (RAW264.7), LP105 inhibited 5-LOX in whole cells (IC50: 1–3 µM) and in supernatants (IC50: ∼10 µM). Oral administration of LP105 to mice resulted in therapeutic tissue and plasma levels. Aortic aneurysms were induced in ApoE−/− mice by angiotensin II (AngII) and LP105 (5 mg·day−1 per animal) was co-administered to a subgroup. Compared with animals receiving AngII alone, the LP105+AngII group showed a lower heart rate, a trend towards reduced heart to body weight ratio but similar hypertensive responses. AngII alone significantly increased aortic weight and diameter but co-treatment with LP105+AngII prevented these changes. LC/MS-MS studies revealed increased 15-hydroxytetraenoic Acid (15-HETE) and 14,15-epoxyeicosatrienoic Acid (14,15-EET) plasma levels in LP105-treated animals. In the murine kidney, mRNAs of EET-generating or metabolizing enzymes and of 5-LOX and 15-LOX were unaffected by LP105. LP105 also did not inhibit the EET-metabolizing soluble epoxide hydrolase. CONCLUSIONS AND IMPLICATIONS LP105 was a potent inhibitor of monocyte 5-LOX and reduced AngII-induced vascular remodelling in mice. A shift of arachidonic Acid metabolism to the protective EET pathway may contribute to the beneficial effects of LP105.
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Interference of alpha-alkyl-substituted Pirinixic Acid derivatives with neutrophil functions and signalling pathways.
European journal of pharmacology, 2009Co-Authors: Daniel Poeckel, Laura Popescu, Oliver Rau, Manfred Schubert-zsilavecz, Christine Greiner, Carlo Pergola, Arne Henkel, Oliver WerzAbstract:Pirinixic Acid (Wy-14,643) is an agonist of the peroxisome proliferator-activated receptor (PPAR) subtype alpha exhibiting beneficial effects in various inflammation-related processes in a slow, long-termed fashion. We recently showed that alpha-substituted Pirinixic Acid derivatives are agonists of PPAR alpha and act as dual inhibitors of 5-lipoxygenase (5-LO, EC 1.13.11.34) and the microsomal prostaglandin E(2) synthase-1 (EC 5.3.99.3). Here, we explored short-term effects of alpha-substituted Pirinixic Acid derivatives on typical neutrophil functions evoked by the agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP) including leukotriene formation, generation of reactive oxygen species, and release of human leukocyte elastase (EC 3.4.21.37), and we investigated the modulation of related signalling pathways. Pirinixic Acid derivatives that are substituted with alkyl residues in alpha-position of the carboxylic group and with a 6-aminoquinoline residue at the pyrimidine moiety cause inhibition of leukotriene formation, reactive oxygen species formation, and leukocyte elastase release in response to fMLP. In parallel, Ca(2+) mobilisation and the phosphorylation (activation) of p38 mitogen-activated protein kinase was significantly reduced, whereas phosphorylation of the extracellular signal-regulated kinase-2 was unaffected. Pirinixic Acid itself was not or only marginally active in all these assays. Conclusively, targeted structural modification of Pirinixic Acid leads to bioactive compounds that display immediate anti-inflammatory properties in human neutrophils with potential therapeutic value.
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Interference of α-alkyl-substituted Pirinixic Acid derivatives with neutrophil functions and signalling pathways
European Journal of Pharmacology, 2009Co-Authors: Daniel Poeckel, Laura Popescu, Oliver Rau, Manfred Schubert-zsilavecz, Christine Greiner, Carlo Pergola, Arne Henkel, Oliver WerzAbstract:Pirinixic Acid (Wy-14,643) is an agonist of the peroxisome proliferator-activated receptor (PPAR) subtype alpha exhibiting beneficial effects in various inflammation-related processes in a slow, long-termed fashion. We recently showed that alpha-substituted Pirinixic Acid derivatives are agonists of PPAR alpha and act as dual inhibitors of 5-lipoxygenase (5-LO, EC 1.13.11.34) and the microsomal prostaglandin E(2) synthase-1 (EC 5.3.99.3). Here, we explored short-term effects of alpha-substituted Pirinixic Acid derivatives on typical neutrophil functions evoked by the agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP) including leukotriene formation, generation of reactive oxygen species, and release of human leukocyte elastase (EC 3.4.21.37), and we investigated the modulation of related signalling pathways. Pirinixic Acid derivatives that are substituted with alkyl residues in alpha-position of the carboxylic group and with a 6-aminoquinoline residue at the pyrimidine moiety cause inhibition of leukotriene formation, reactive oxygen species formation, and leukocyte elastase release in response to fMLP. In parallel, Ca(2+) mobilisation and the phosphorylation (activation) of p38 mitogen-activated protein kinase was significantly reduced, whereas phosphorylation of the extracellular signal-regulated kinase-2 was unaffected. Pirinixic Acid itself was not or only marginally active in all these assays. Conclusively, targeted structural modification of Pirinixic Acid leads to bioactive compounds that display immediate anti-inflammatory properties in human neutrophils with potential therapeutic value.
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Novel and potent inhibitors of 5-lipoxygenase product synthesis based on the structure of Pirinixic Acid.
Journal of medicinal chemistry, 2008Co-Authors: Oliver Werz, Laura Popescu, Manfred Schubert-zsilavecz, Christine Greiner, Andreas Koeberle, Christina Hoernig, Sven George, Ivonne Syha, Dieter SteinhilberAbstract:A novel class of potent 5-lipoxygenase (5-LO) product synthesis inhibitors based on the structure of Pirinixic Acid (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic Acid, compound 1) is presented. Systematic profiling of 1, i.e., esterification of the carboxylic Acid, alpha-substitution, and replacement of the o-dimethylaniline by 6-aminoquinoline, leads to potent suppressors of 5-LO product formation in activated polymorphonuclear leukocytes, exemplified by ethyl 2-[4-chloro-6-(quinoline-6-ylamino)-pyrimidin-2-ylsulfanyl]octane-1-carboxylate (6d, IC50 = 0.6 microM). These derivatives may possess potential for intervention with inflammatory and allergic diseases.
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quinoline based derivatives of Pirinixic Acid as dual ppar α γ agonists
Archiv Der Pharmazie, 2007Co-Authors: Laura Popescu, Oliver Rau, Jark Böttcher, Yvonne Syha, Manfred SchubertzsilaveczAbstract:Pirinixic Acid is known for its peroxisome proliferator-activated receptor (PPAR) agonistic action. In a recent publication, we have shown that aliphatic alpha-substitution of Pirinixic Acid enhances both PPARalpha and PPARgamma agonism. The goal of this study was to evaluate, whether the PPAR agonism of Pirinixic Acid may be also maintained in quinoline-based derivatives. The present study revealed that the mere substitution of the dimethyl aniline moiety of Pirinixic Acid by quinoline leads to a total loss of PPARalpha/gamma agonism, whereas concomitant alpha-substitution with n-butyl or n-hexyl groups restores and even enforces PPAR activation, leading to potent dual PPARalpha/gamma agonists. In the following we report the synthesis of quinoline-based derivatives of Pirinixic Acid, which in a Gal4-based luciferase-reporter gene assay proved to be potent dual PPARalpha/gamma agonists. Molecular docking of compound 4 with FlexX suggests a binding mode resembling to that of tesaglitazar.