Please use this identifier to cite or link to this item: https://doi.org/10.1124/jpet.111.181354
Title: Development of a high-affinity inhibitor of the prostaglandin transporter
Authors: Chi, Y.
Min, J.
Jasmin, J.-F.
Lisanti, M.P.
Chang, Y.-T. 
Schuster, V.L.
Issue Date: Nov-2011
Citation: Chi, Y., Min, J., Jasmin, J.-F., Lisanti, M.P., Chang, Y.-T., Schuster, V.L. (2011-11). Development of a high-affinity inhibitor of the prostaglandin transporter. Journal of Pharmacology and Experimental Therapeutics 339 (2) : 633-641. ScholarBank@NUS Repository. https://doi.org/10.1124/jpet.111.181354
Abstract: Prostaglandin E 2 (PGE 2) triggers a vast array of biological signals and physiological events. The prostaglandin transporter (PGT) controls PGE2 influx and is rate-limiting for PGE 2 metabolism and signaling termination. PGT global knockout mice die on postnatal day 1 from patent ductus arteriosus. A high-affinity PGT inhibitor would thus be a powerful tool for studying PGT function in adult animals. Moreover, such an inhibitor could be potentially developed into a therapeutic drug targeting PGT. Based on structure-activity relationship studies that built on recently identified inhibitors of PGT, we obtained N-(2- (2-(2-azidoethoxy)ethoxy)ethyl)-4-((4-((2- (2-(2-benzamidoethoxy) ethoxy)ethyl)amino)-6-((4-hydroxyphenyl)amino)-1,3,5- triazin-2- yl)amino)benzamide (T26A), a competitive inhibitor of PGT, with a K i of 378 nM. T26A seems to be highly selective for PGT, because it neither interacts with a PGT homolog in the organic anion transporter family nor affectsPGE 2 synthesis. In Madin-Darby canine kidney cells stably transfected with PGT, T26A blocked PGE 2 metabolism, resulting in retention of PGE 2 in the extracellular compartment and the negligible appearance of PGE 2 metabolites in the intracellular compartment. Compared with vehicle, T26A injected intravenously into rats effectively doubled the amount of endogenous PGE 2 in the circulation and reduced the level of circulating endogenous PGE 2 metabolites to 50%. Intravenous T26A was also able to slow the metabolism of exogenously injected PGE 2. These results confirm that PGT directly regulates PGE 2 metabolism and demonstrate that a high-affinity inhibitor of PGT can effectively prevent PGE 2 metabolism and prolong the half-life of circulating PGE 2. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.
Source Title: Journal of Pharmacology and Experimental Therapeutics
URI: http://scholarbank.nus.edu.sg/handle/10635/93573
ISSN: 00223565
DOI: 10.1124/jpet.111.181354
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

16
checked on Jun 8, 2021

WEB OF SCIENCETM
Citations

13
checked on Jun 8, 2021

Page view(s)

76
checked on Jun 8, 2021

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.