A new family of thromboxane receptor antagonists with secondary thromboxane synthase inhibition.
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-[1alpha,2alpha(Z),3beta(1E,3S*),4alpha]]-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-9alpha,11alpha-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 IC(50) versus aggregation by I-BOP = 0.6 x 10(-7) M and versus U46619 = 7 x 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 IC(50) = 8 x 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 A(2), 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 (125)I-BOP, where the IC(50) for PBT-3 was 8 x 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.
Pace-Asciak
Cecil R
CR
Programme in Integrative Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada. pace@sickkids.on.ca
Reynaud
Denis
D
Demin
Peter
P
Aslam
Rukshana
R
Sun
Andrea
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D010741:Phospholipases A / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D007527:Isoenzymes; D008565:Membrane Proteins; C453725:PBT-3 compound; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000242:Cyclic AMP; D001092:Arachidonate 12-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D013930:Thromboxane-A Synthase; D015126:8,11,14-Eicosatrienoic Acid