Novel Highly Potent and Metabolically Resistant Oxoeicosanoid (OXE) Receptor Antagonists That Block the Actions of the Granulocyte Chemoattractant 5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE)
| Autor: | Chintam Nagendra Reddy, William S. Powell, Rui Wang, Irina Slobodchikova, Dajana Vuckovic, Chantal Cossette, Qiuji Ye, Shishir Chourey, Joshua Rokach, Sylvie Gravel |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Metabolite Eicosatetraenoic acid Arachidonic Acids Pharmacology Inhibitory Concentration 50 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Eosinophil activation Animals Humans Tissue Distribution Pentanoic Acids Oxoeicosanoid Receptor IC50 Indole test Chemotactic Factors Antagonist Stereoisomerism 3. Good health Macaca fascicularis 030104 developmental biology chemistry Receptors Eicosanoid Molecular Medicine Calcium Female Granulocytes 030215 immunology |
| Zdroj: | Journal of Medicinal Chemistry. 61:5934-5948 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b00154 |
| Popis: | 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a potent lipid mediator that induces tissue eosinophilia via the selective OXE receptor (OXE-R), which is an attractive therapeutic target in eosinophilic diseases. We previously identified indole OXE-R antagonists that block 5-oxo-ETE-induced primate eosinophil activation. Although these compounds possess good oral absorption, their plasma levels decline rapidly due to extensive oxidation of their hexyl side chain. We have now succeeded in dramatically increasing antagonist potency and resistance to metabolism by replacing the hexyl group with phenylpentyl or phenylhexyl side chains. Compared with our previous lead compound S-230, our most potent antagonist, S-C025, has an IC50 (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC50, 690 pM) and has a prolonged lifetime in plasma was observed. These new highly potent OXE-R antagonists may provide a novel strategy for t... |
| Databáze: | OpenAIRE |
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