| Autor: |
Chourey S; Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology , 150 West University Boulevard , Melbourne , Florida 32901-6982 , United States., Ye Q; Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology , 150 West University Boulevard , Melbourne , Florida 32901-6982 , United States., Reddy CN; Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology , 150 West University Boulevard , Melbourne , Florida 32901-6982 , United States., Wang R; Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology , 150 West University Boulevard , Melbourne , Florida 32901-6982 , United States., Cossette C; Meakins-Christie Laboratories, Centre for Translational Biology , McGill University Health Centre , 1001 Decarie Boulevard , Montreal , Quebec H4A 3J1 , Canada., Gravel S; Meakins-Christie Laboratories, Centre for Translational Biology , McGill University Health Centre , 1001 Decarie Boulevard , Montreal , Quebec H4A 3J1 , Canada., Slobodchikova I; Department of Chemistry and Biochemistry and PERFORM Centre , Concordia University , 7141 Sherbrooke Street West , Montréal , Quebec H4B 1R6 , Canada., Vuckovic D; Department of Chemistry and Biochemistry and PERFORM Centre , Concordia University , 7141 Sherbrooke Street West , Montréal , Quebec H4B 1R6 , Canada., Rokach J; Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology , 150 West University Boulevard , Melbourne , Florida 32901-6982 , United States., Powell WS; Meakins-Christie Laboratories, Centre for Translational Biology , McGill University Health Centre , 1001 Decarie Boulevard , Montreal , Quebec H4A 3J1 , Canada. |
| Abstrakt: |
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 IC 50 (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC 50 , 690 pM) and has a prolonged lifetime in plasma was observed. These new highly potent OXE-R antagonists may provide a novel strategy for the treatment of eosinophilic disorders like asthma. |
