RT Journal Article
SR Electronic
T1 A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 618
OP 624
DO 10.1124/jpet.301.2.618
VO 301
IS 2
A1 Cecil R. Pace-Asciak
A1 Denis Reynaud
A1 Peter Demin
A1 Rukshana Aslam
A1 Andrea Sun
YR 2002
UL http://jpet.aspetjournals.org/content/301/2/618.abstract
AB We report herein a novel class of thromboxane receptor (TP receptor) antagonists modeled on unstable natural lipids that we identified several years ago, the hepoxilins. These antagonists have been rendered chemically and biologically more stable than the natural compounds through structural modification by chemical synthesis. We demonstrate that the analogs inhibit the aggregation of human platelets in vitro evoked by the thromboxane receptor agonists, I-BOP ([1S-[1α,2α(Z),3β(1E,3S*),4α]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabi-cyclo[2.2.1]hept-2-yl]5-heptenoic acid) and U46619(9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid). The most potent of the analogs described, PBT-3 [10(S)-hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z-trienoic acid methyl ester], has an IC50 versus aggregation by I-BOP = 0.6 × 10−7 M and versus U46619 = 7 × 10−7 M, representing one of the most potent anti-aggregating substances so far described. PBT-3 also inhibits thromboxane formation and aggregation evoked by collagen with an IC50 = 8 × 10−7 M. Other PBT (hepoxilin cyclopropane) analogs so far tested were 5- to 10-fold less active, and the native hepoxilins were about 500-fold less active. Neither PBT-3 nor the other analogs inhibited 12-lipoxygenase, phospholipase A2, or cyclooxygenase 1 or 2, and weakly stimulated adenyl cyclase (threshold stimulation at 10−7 M and little selectivity for each of the PBT compounds). TP antagonism by PBT-3 was further demonstrated in receptor binding studies through use of 125I-BOP, where the IC50 for PBT-3 was 8 × 10−9 M, approximately 16-fold less than for I-BOP itself. These findings identify a new mode of action of PBT-3 and other related analogs as primarily TP antagonists. These studies identify a new family of compounds useful in further development as novel therapeutics for thromboxane-mediated diseases. The American Society for Pharmacology and Experimental Therapeutics