title: Development of a high-affinity inhibitor of the prostaglandin transporter.
abstract: Prostaglandin E(2) (PGE(2)) triggers a vast array of biological signals and physiological events. The prostaglandin transporter (PGT) controls PGE(2) 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 affects PGE(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).
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer 1008, Bronx, NY 10461, USA.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chi
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Jasmin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Chang
authors.forename: Victor L
authors.initials: VL
authors.lastname: Schuster
mesh_terms: D010129:4-Aminobenzoic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D035061:Control Groups; D015232:Dinoprostone / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy*; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062366:para-Aminobenzoates
chemical_list: C569290: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; D027361:Organic Anion Transporters; C503526:SLCO2A1 protein, human; D014227:Triazines; D062366:para-Aminobenzoates; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D010129:4-Aminobenzoic Acid