title: 6,6-Disubstituted Hex-5-enoic acid derivatives as combined thromboxane A2 receptor antagonists and synthetase inhibitors.
abstract: A series of omega-disubstituted alkenoic acid derivatives were designed and synthesized as antithrombotic inhibitors of thromboxane A2 synthetase and thromboxane A2 receptor antagonists. Hexenoic acid derivatives with a 3-pyridyl group and a 4-(2-benzenesulfonamidoethyl)phenyl substituent were found to be optimal with regard to the dual mode of action. The most potent compound, (E)-6-(4-(2-(((4-chlorophenyl)sulfonyl)amino)ethyl)phenyl)-6-(3-pyridyl) hex-5-enoic acid (36), inhibits thromboxane A2 synthetase in gel-filtered human platelets with an IC50 value of 4.5 +/- 0.5 nM (n = 4), whereas an inhibitory effect on cyclooxygenase is seen only at a much higher concentration (IC50: 240 microM). Radioligand-binding studies with [3H]SQ 29,548 in washed human platelets revealed that 36 blocks the prostaglandin H2/thromboxane A2 receptor with an IC50 of 19 +/- 5 nM (n = 5) and is therefore 85-fold more potent than another combined thromboxane A2 synthetase inhibitor/receptor antagonist, Ridogrel (4). Compound 36 inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an EC50 of 1 microM (Ridogrel: 16 microM) and 100 nM, respectively, and was selected for further development.
authors.affiliation: Research Department, Dr. Karl Thomae GmbH, Biberach, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Soyka
authors.forename: A
authors.initials: A
authors.lastname: Heckel
authors.forename: J
authors.initials: J
authors.lastname: Nickl
authors.forename: W
authors.initials: W
authors.lastname: Eisert
authors.forename: T H
authors.initials: TH
authors.lastname: Müller
authors.forename: H
authors.initials: H
authors.lastname: Weisenberger
mesh_terms: D001792:Blood Platelets / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003094:Collagen / Q000494:pharmacology; D015195:Drug Design; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000737:chemistry; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000097:blood; D014316:Tritium
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D017482:Receptors, Thromboxane; D014316:Tritium; C085366:6-(4-(2-(((4-chlorophenyl)sulfonyl)amino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoic acid; D013928:Thromboxane A2; C045749:SQ 29548; D003094:Collagen; D013930:Thromboxane-A Synthase