6,6-Disubstituted Hex-5-enoic acid derivatives as combined thromboxane A2 receptor antagonists and synthetase inhibitors.
Article Details
- CitationCopy to clipboard
Soyka R, Heckel A, Nickl J, Eisert W, Muller TH, Weisenberger H
6,6-Disubstituted Hex-5-enoic acid derivatives as combined thromboxane A2 receptor antagonists and synthetase inhibitors.
J Med Chem. 1994 Jan 7;37(1):26-39.
- PubMed ID
- 8289199 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Ridogrel Thromboxane A2 receptor Protein Humans YesAntagonistDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Ridogrel Thromboxane A2 receptor IC 50 (nM) 1700 N/A N/A Details Ridogrel Thromboxane A2 receptor IC 50 (nM) 5200 N/A N/A Details Ridogrel Thromboxane-A synthase IC 50 (nM) 8 N/A N/A Details Ridogrel Thromboxane-A synthase IC 50 (nM) 4 N/A N/A Details