Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor

J M Dogné; J Wouters; S Rolin; C Michaux; L Pochet; F Durant; J Delarge; B Masereel

doi:10.1211/0022357011775992

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A₂ receptor antagonist and thromboxane synthase inhibitor

J M Dogné, J Wouters, S Rolin, C Michaux, L Pochet, F Durant, J Delarge, B Masereel

Research output: Contribution to journal › Article › peer-review

Abstract

The synthesis and the structure of N-isopropyl-N′-[2-(3′-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A₂ receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A₂ (TXA₂) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 μM) with an IC50 value of 0.45 and 0.15 μM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA₂ agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 μM) completely inhibited TXA₂ synthase of human platelets. The pK_a value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA₂ antagonists related to torasemide and their receptor.

Original language	English
Pages (from-to)	669-80
Number of pages	12
Journal	Journal of Pharmacy and Pharmacology
Volume	53
Issue number	5
DOIs	https://doi.org/10.1211/0022357011775992
Publication status	Published - 1 May 2001

Keywords

Animals
Aorta
Arachidonic Acid
Guinea Pigs
Male
Platelet Aggregation
Rats
Rats, Wistar
Receptors, Thromboxane
Sulfonylurea Compounds
Thromboxane-A Synthase
Trachea

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title = "Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor",

abstract = "The synthesis and the structure of N-isopropyl-N′-[2-(3′-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 μM) with an IC50 value of 0.45 and 0.15 μM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 μM) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.",

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author = "Dogn{\'e}, {J M} and J Wouters and S Rolin and C Michaux and L Pochet and F Durant and J Delarge and B Masereel",

year = "2001",

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T1 - Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor

AU - Dogné, J M

AU - Wouters, J

AU - Rolin, S

AU - Michaux, C

AU - Pochet, L

AU - Durant, F

AU - Delarge, J

AU - Masereel, B

PY - 2001/5/1

Y1 - 2001/5/1

N2 - The synthesis and the structure of N-isopropyl-N′-[2-(3′-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 μM) with an IC50 value of 0.45 and 0.15 μM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 μM) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.

AB - The synthesis and the structure of N-isopropyl-N′-[2-(3′-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 μM) with an IC50 value of 0.45 and 0.15 μM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 μM) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.

KW - Animals

KW - Aorta

KW - Arachidonic Acid

KW - Guinea Pigs

KW - Male

KW - Platelet Aggregation

KW - Rats

KW - Rats, Wistar

KW - Receptors, Thromboxane

KW - Sulfonylurea Compounds

KW - Thromboxane-A Synthase

KW - Trachea

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DO - 10.1211/0022357011775992

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JO - Journal of Pharmacy and Pharmacology

JF - Journal of Pharmacy and Pharmacology

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ER -

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A₂ receptor antagonist and thromboxane synthase inhibitor

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