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  • 1
    Language: English
    In: Future medicinal chemistry, December 2011, Vol.3(16), pp.1969-70
    Keywords: Cystic Fibrosis -- Therapy
    ISSN: 17568919
    E-ISSN: 1756-8927
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  • 2
    Language: English
    In: Bioorganic & Medicinal Chemistry Letters, 15 August 2014, Vol.24(16), pp.4048-4052
    Description: Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARα and PPARγ agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARα particularly dual PPARα/γ agonists with 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid having the highest potential. Our investigations based on molecular docking and structure–activity relationship (SAR) studies elucidated structural determinants affecting the potency at PPARα. A diphenylamine-scaffold seems to play a key role. Careful in silico analysis revealed an essential role for a hydrogen bond between the diphenylamine and a water cluster. We confirmed this hypothesis using a mutated PPARα LBD in our transactivation assay to disrupt the water cluster and to validate the proposed interaction.
    Keywords: Metabolic Syndrome ; Peroxisome Proliferator-Activated Receptor ; Dual Pparα/Γ Agonist ; Structure–Activity Relationship ; Site-Directed Mutagenesis ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0960-894X
    E-ISSN: 1464-3405
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  • 3
    Language: English
    In: Bioorganic & Medicinal Chemistry Letters, 15 August 2014, Vol.24(16), pp.3757-3763
    Description: 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 E 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 , (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid)). Therefore, docking of on PPARγ was performed to determine the potential binding mode.
    Keywords: Pparα ; Pparγ ; Inflammation ; 5-Lo ; Mpges-1 ; Cancer ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0960-894X
    E-ISSN: 1464-3405
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  • 4
    Language: English
    In: Pharmazie in unserer Zeit, 01/2011, Vol.40(1), pp.2-2
    ISSN: Pharmazie in unserer Zeit
    E-ISSN: 00483664
    Source: Wiley (via CrossRef)
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  • 5
    Language: German
    In: Pharmazie in unserer Zeit, January 2011, Vol.40(1), pp.2
    Keywords: Societies, Pharmaceutical
    ISSN: 00483664
    E-ISSN: 1615-1003
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    Language: English
    In: Journal of medicinal chemistry, 26 April 2012, Vol.55(8), pp.3792-803
    Description: Microsomal prostaglandin E synthase 1 (mPGES-1) is a key enzyme of the arachidonic acid cascade. Its product PGE(2) plays an important role in various inflammatory processes, pain, fever, and cancer. Selective inhibition of mPGES-1 might be a promising step to avoid cyclooxygenase-related effects of NSAIDs. We studied a class of quinazolinone derivatives of the lead structure FR20 for their effects on the isolated human and murine enzymes, human HeLa cells, and in various settings of the whole blood assay. Novel compounds with direct enzyme inhibiting activity in the submicromolar range (IC(50): 0.13-0.37 μM) were designed using a bioisosteric replacement strategy and proved to be effective in both cells and human whole blood. Furthermore, pharmacological profiling of toxicity and eicosanoid screening with LC/MS-MS was applied to characterize this new class of mPGES-1 inhibitors.
    Keywords: Enzyme Inhibitors -- Pharmacology ; Intramolecular Oxidoreductases -- Antagonists & Inhibitors ; Quinazolinones -- Pharmacology
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 7
    Language: English
    In: Journal of medicinal chemistry, 13 December 2012, Vol.55(23), pp.10771-5
    Description: Metabolic syndrome is a complex condition which often requires the use of multiple medications as a treatment. The resulting problems of polypharmacy are increase in side effects, drug-drug interactions, and its high economic cost. Development of multitarget compounds is a promising strategy to avoid the complications arising from administration of multiple drugs. Modulators of peroxisome proliferator-activated receptors (PPARs) are established agents in the treatment of dyslipidaemia, hyperglycaemia, and insulin resistance. Inhibitors of soluble epoxide hydrolase (sEH) are under evaluation for their use in cardiovascular diseases. In the present study, a series of dual sEH/PPAR modulators containing a pyrrole acidic headgroup and a urea pharmacophore were designed, synthesized, and evaluated in vitro using recombinant enzyme and cell-based assays. Compounds with different activity profiles were obtained which could be used in the treatment of metabolic syndrome.
    Keywords: Epoxide Hydrolases -- Chemical Synthesis ; Peroxisome Proliferator-Activated Receptors -- Chemistry
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 8
    Language: English
    In: Journal of medicinal chemistry, 09 October 2014, Vol.57(19), pp.8035-55
    Description: The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor to the full extent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells.
    Keywords: Receptors, Cytoplasmic and Nuclear -- Agonists ; Ortho-Aminobenzoates -- Chemical Synthesis
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 9
    Language: English
    In: Journal of medicinal chemistry, 10 May 2018, Vol.61(9), pp.3930-3938
    Description: Rhabdopeptides are a large class of nonribosomal peptides from the bacteria Xenorhabdus and Photorhabdus with low micromolar activity against different protozoa, which are the causative agents of several tropical diseases. The development of a facile and flexible synthesis combining backbone amide linking with on-resin peralkylation for the synthesis of permethylated rhabdopeptides is described. This strategy allows the fast generation of permethylated naturally occurring and artificial rhabdopeptides for a structure-activity study. Furthermore, in vitro experiments revealed their superior properties regarding their stability and passive membrane diffusion.
    Keywords: Amides -- Chemistry ; Antiprotozoal Agents -- Chemistry ; Peptides -- Chemistry
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 10
    Language: English
    In: Journal of medicinal chemistry, 14 July 2011, Vol.54(13), pp.4490-507
    Description: Various inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E(2) synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of the structure of 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid (1), we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition. Interestingly, the pyrimidine ring including the thioether of 1 could be replaced by a simple benzyl or a benzylidene moiety yielding a novel series of bioactive 2-benzylidene- and 2-benzylhexanoic acids exemplified by 2-(2,3-diphenethoxybenzylidene)hexanoic acid, 29 (IC(50) 5-LO = 0.8 μM; mPGES-1 = 1.1 μM). Importantly, none of the novel bioactive derivatives strongly inhibited cyclooxygenase activities. Together, we provide novel promising lead compounds for the treatment of inflammatory diseases valuable for further investigations in vivo.
    Keywords: Anti-Inflammatory Agents, Non-Steroidal -- Chemical Synthesis ; Benzene Derivatives -- Chemical Synthesis ; Caproates -- Chemical Synthesis ; Intramolecular Oxidoreductases -- Antagonists & Inhibitors ; Lipoxygenase Inhibitors -- Chemical Synthesis ; Microsomes -- Enzymology ; Pyrimidines -- Chemical Synthesis
    ISSN: 00222623
    E-ISSN: 1520-4804
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