| 1-(5-Carboxyindol-1-yl)propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha: synthesis and properties of bioisosteric benzimidazole, benzotriazole and indazole analogues. | |
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MedLine Citation:
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PMID: 19327988 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The indole ring systems of the cytosolic phospholipase A(2)alpha (cPLA(2)alpha) inhibitor 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (2) and the isomeric 6-carboxylic acid (3) were replaced by benzimidazole, benzotriazole and indazole scaffolds, respectively. The effect of the structural variations on cPLA(2)alpha inhibitory potency, metabolic stability and solubility was studied. The lead 2 and the indazole-5-carboxylic acid 28 were the metabolically most stable compounds in an assay with rat liver microsomes, while the benzimidazole-5-carboxylic acid derivative 13 possessed the best water solubility (22 microg/mL at pH 7.4). The indazole-5-carboxylic acid 28 revealed the highest cPLA(2)alpha inhibitory potency of the compounds in this series. With an IC(50)-value of 0.005 microM it was about sevenfold more active than the lead 2. |
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Authors:
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Stefanie Bovens; Martina Kaptur; Alwine Schulze Elfringhoff; Matthias Lehr |
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Publication Detail:
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Type: Comparative Study; Journal Article Date: 2009-03-10 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 19 ISSN: 1464-3405 ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-04-03 Completed Date: 2009-08-26 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: England |
Other Details:
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Languages: eng Pagination: 2107-11 Citation Subset: IM |
Affiliation:
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Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Benzimidazoles
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chemical synthesis*,
pharmacology Cytosol / drug effects, enzymology* Group IV Phospholipases A2 / antagonists & inhibitors*, metabolism Humans Indazoles / chemical synthesis*, pharmacology Indoles / chemical synthesis*, pharmacology Propionic Acids / chemical synthesis*, pharmacology Stereoisomerism Triazoles / chemical synthesis*, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/1-(5-carboxyindol-1-yl)propan-2-one; 0/Benzimidazoles; 0/Indazoles; 0/Indoles; 0/Propionic Acids; 0/Triazoles; 27556-51-0/benzotriazole; 51-17-2/benzimidazole; EC 3.1.1.4/Group IV Phospholipases A2 |
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