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Thomas Muller - One of the best experts on this subject based on the ideXlab platform.
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guanidine derivatives as combined thromboxane a2 receptor antagonists and synthase inhibitors
Journal of Medicinal Chemistry, 1999Co-Authors: Rainer Soyka, Brian D Guth, H Weisenberger, Peter Luger, Thomas MullerAbstract:A new series of ω-disubstituted alkenoic acid derivatives derived from samixogrel 5 were designed and synthesized as combined thromboxane A2 receptor antagonists/thromboxane A2 synthase inhibitors with improved solubility and reduced protein binding compared to 5. Hexenoic acid derivatives with a 3-Pyridyl Group and 3-(2-cyano-3-alkyl-guanidino)phenyl substituent were found to be optimal with regard to this dual mode of action. The most potent compound, E-6-(3-(2-cyano-3-tert-butyl-guanidino)phenyl)-6-(3-Pyridyl)hex-5-enoic acid, “terbogrel” 32 inhibits the thromboxane A2 synthase in human gel-filtered platelets with an IC50 value of 4.0 ± 0.5 nM (n = 4). Radioligand binding studies with 3H-SQ 29,548 revealed that 32 blocks the thromboxane A2/endoperoxide receptor on washed human platelets with an IC50 of 11 ± 6 nM (n = 2) and with an IC50 of 38 ± 1 nM (n = 15) in platelet-rich plasma. Terbogrel inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an IC50 o...
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6 6 disubstituted hex 5 enoic acid derivatives as combined thromboxane a2 receptor antagonists and synthetase inhibitors
Journal of Medicinal Chemistry, 1994Co-Authors: Rainer Soyka, Thomas Muller, Armin Heckel, J Nickl, W Eisert, H WeisenbergerAbstract: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.
H Weisenberger - One of the best experts on this subject based on the ideXlab platform.
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guanidine derivatives as combined thromboxane a2 receptor antagonists and synthase inhibitors
Journal of Medicinal Chemistry, 1999Co-Authors: Rainer Soyka, Brian D Guth, H Weisenberger, Peter Luger, Thomas MullerAbstract:A new series of ω-disubstituted alkenoic acid derivatives derived from samixogrel 5 were designed and synthesized as combined thromboxane A2 receptor antagonists/thromboxane A2 synthase inhibitors with improved solubility and reduced protein binding compared to 5. Hexenoic acid derivatives with a 3-Pyridyl Group and 3-(2-cyano-3-alkyl-guanidino)phenyl substituent were found to be optimal with regard to this dual mode of action. The most potent compound, E-6-(3-(2-cyano-3-tert-butyl-guanidino)phenyl)-6-(3-Pyridyl)hex-5-enoic acid, “terbogrel” 32 inhibits the thromboxane A2 synthase in human gel-filtered platelets with an IC50 value of 4.0 ± 0.5 nM (n = 4). Radioligand binding studies with 3H-SQ 29,548 revealed that 32 blocks the thromboxane A2/endoperoxide receptor on washed human platelets with an IC50 of 11 ± 6 nM (n = 2) and with an IC50 of 38 ± 1 nM (n = 15) in platelet-rich plasma. Terbogrel inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an IC50 o...
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6 6 disubstituted hex 5 enoic acid derivatives as combined thromboxane a2 receptor antagonists and synthetase inhibitors
Journal of Medicinal Chemistry, 1994Co-Authors: Rainer Soyka, Thomas Muller, Armin Heckel, J Nickl, W Eisert, H WeisenbergerAbstract: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.
Rainer Soyka - One of the best experts on this subject based on the ideXlab platform.
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guanidine derivatives as combined thromboxane a2 receptor antagonists and synthase inhibitors
Journal of Medicinal Chemistry, 1999Co-Authors: Rainer Soyka, Brian D Guth, H Weisenberger, Peter Luger, Thomas MullerAbstract:A new series of ω-disubstituted alkenoic acid derivatives derived from samixogrel 5 were designed and synthesized as combined thromboxane A2 receptor antagonists/thromboxane A2 synthase inhibitors with improved solubility and reduced protein binding compared to 5. Hexenoic acid derivatives with a 3-Pyridyl Group and 3-(2-cyano-3-alkyl-guanidino)phenyl substituent were found to be optimal with regard to this dual mode of action. The most potent compound, E-6-(3-(2-cyano-3-tert-butyl-guanidino)phenyl)-6-(3-Pyridyl)hex-5-enoic acid, “terbogrel” 32 inhibits the thromboxane A2 synthase in human gel-filtered platelets with an IC50 value of 4.0 ± 0.5 nM (n = 4). Radioligand binding studies with 3H-SQ 29,548 revealed that 32 blocks the thromboxane A2/endoperoxide receptor on washed human platelets with an IC50 of 11 ± 6 nM (n = 2) and with an IC50 of 38 ± 1 nM (n = 15) in platelet-rich plasma. Terbogrel inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an IC50 o...
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6 6 disubstituted hex 5 enoic acid derivatives as combined thromboxane a2 receptor antagonists and synthetase inhibitors
Journal of Medicinal Chemistry, 1994Co-Authors: Rainer Soyka, Thomas Muller, Armin Heckel, J Nickl, W Eisert, H WeisenbergerAbstract: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.
Hans Weissenberger - One of the best experts on this subject based on the ideXlab platform.
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On the bioisosteric potential of diazines: diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor Ridogrel.
Journal of medicinal chemistry, 1996Co-Authors: Gottfried Heinisch, Wolfgang Holzer, Friedbert Kunz, Thierry Langer, P. Lukavsky, Christoph Pechlaner, Hans WeissenbergerAbstract:In this SAR study the bioisosteric potential of diazines in the field of combined antithrombotic thromboxane A2 synthetase inhibitors and receptor antagonists was investigated. In this context, two series of (E)- and (Z)-ω-[[(aryldiazinylmethylene)amino]oxy]alkanoic acids were synthesized of which pentanoic acid derivatives with a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl Group were found to exhibit this dual activity, while 4-pyrimidinyl as well as 3-pyridazinyl analogues showed only receptor antagonistic activity and 2-pyrimidinyl congeners were inactive. In the series of diazine analogues of Ridogrel (1), replacement of the 3-Pyridyl Group by a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl moiety led to compounds that inhibit thromboxane A2 synthetase in gel-filtered human platelets comparable to 1 (IC50 of 0.006, 0.016, and 0.039 μM, respectively, versus 0.007 μM). Radioligand-binding studies with [3H]SQ 29,548 in washed human platelets revealed that these diazine analogues block the thromboxane A2 ...
Ruth Jackson - One of the best experts on this subject based on the ideXlab platform.
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dual acting thromboxane receptor antagonist synthase inhibitors synthesis and biological properties of 2 substituted 4 3 pyridyl 1 3 dioxan 5 yl alkenoic acids
Journal of Medicinal Chemistry, 1995Co-Authors: Alan Wellington Faull, Andrew George Brewster, George R Brown, Michael James Smithers, Ruth JacksonAbstract:: The design, synthesis, and pharmacology of a new class of compounds possessing both thromboxane receptor antagonist and thromboxane synthase inhibitory properties are described. Replacement of the phenol Group of the known thromboxane antagonist series 4(Z)-6-[(4RS,5SR)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl] hex-4-enoic acid by a 3-Pyridyl Group led to a series of compounds, 5, which were potent thromboxane synthase inhibitors and weak thromboxane antagonists. Further modifications at the dioxane C2 position led to compounds, 7, which were potent dual-acting agents. In the case of compound 7w, the dual activity was shown to reside almost exclusively in the (-)-enantiomer, 7x. Following oral dosing to rats and dogs, 7x (3 mg/kg) displayed significant dual activity over a period of at least 8 h.