TY - JOUR T1 - Development of a High-Affinity Inhibitor of the Prostaglandin Transporter JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 633 LP - 641 DO - 10.1124/jpet.111.181354 VL - 339 IS - 2 AU - Yuling Chi AU - Jaeki Min AU - Jean-Francois Jasmin AU - Michael P. Lisanti AU - Young-Tae Chang AU - Victor L. Schuster Y1 - 2011/11/01 UR - http://jpet.aspetjournals.org/content/339/2/633.abstract N2 - Prostaglandin E2 (PGE2) triggers a vast array of biological signals and physiological events. The prostaglandin transporter (PGT) controls PGE2 influx and is rate-limiting for PGE2 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 Ki 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 affects PGE2 synthesis. In Madin-Darby canine kidney cells stably transfected with PGT, T26A blocked PGE2 metabolism, resulting in retention of PGE2 in the extracellular compartment and the negligible appearance of PGE2 metabolites in the intracellular compartment. Compared with vehicle, T26A injected intravenously into rats effectively doubled the amount of endogenous PGE2 in the circulation and reduced the level of circulating endogenous PGE2 metabolites to 50%. Intravenous T26A was also able to slow the metabolism of exogenously injected PGE2. These results confirm that PGT directly regulates PGE2 metabolism and demonstrate that a high-affinity inhibitor of PGT can effectively prevent PGE2 metabolism and prolong the half-life of circulating PGE2. ER -