From the design to the clinical application of thromboxane modulators

Jean-Michel Dogné, Julien Hanson, Xavier de Leval, Domenico Pratico, Cecil R Pace-Asciak, Pierre Drion, Bernard Pirotte, Ke-He Ruan

Research output: Contribution to journalArticle

Abstract

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.
Original languageEnglish
Pages (from-to)903-23
Number of pages21
JournalCurrent Pharmaceutical Design
Volume12
Issue number8
Publication statusPublished - 2006

Fingerprint

Thromboxanes
Thromboxane Receptors
Prostaglandins H
Thromboxane-A Synthase
Pathology
Bronchoconstriction
Drug Design
Prostaglandin-Endoperoxide Synthases
Septic Shock
Pre-Eclampsia
Vasoconstriction
Pulmonary Embolism
Platelet Aggregation
Arachidonic Acid
Atherosclerosis
Thrombosis
Asthma
Myocardial Infarction
Neoplasm Metastasis
Lung

Keywords

  • Animals
  • Atherosclerosis
  • Blood Platelets
  • Diabetic Retinopathy
  • Drug Design
  • Enzyme Inhibitors
  • Humans
  • Myocardial Infarction
  • Neoplasms
  • Neovascularization, Pathologic
  • Platelet Aggregation
  • Prostaglandins
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Structure-Activity Relationship
  • Sulfonamides
  • Thromboxane A2
  • Thromboxane-A Synthase

Cite this

Dogné, J-M., Hanson, J., de Leval, X., Pratico, D., Pace-Asciak, C. R., Drion, P., ... Ruan, K-H. (2006). From the design to the clinical application of thromboxane modulators. Current Pharmaceutical Design, 12(8), 903-23.
Dogné, Jean-Michel ; Hanson, Julien ; de Leval, Xavier ; Pratico, Domenico ; Pace-Asciak, Cecil R ; Drion, Pierre ; Pirotte, Bernard ; Ruan, Ke-He. / From the design to the clinical application of thromboxane modulators. In: Current Pharmaceutical Design. 2006 ; Vol. 12, No. 8. pp. 903-23.
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abstract = "Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.",
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Dogné, J-M, Hanson, J, de Leval, X, Pratico, D, Pace-Asciak, CR, Drion, P, Pirotte, B & Ruan, K-H 2006, 'From the design to the clinical application of thromboxane modulators', Current Pharmaceutical Design, vol. 12, no. 8, pp. 903-23.

From the design to the clinical application of thromboxane modulators. / Dogné, Jean-Michel; Hanson, Julien; de Leval, Xavier; Pratico, Domenico; Pace-Asciak, Cecil R; Drion, Pierre; Pirotte, Bernard; Ruan, Ke-He.

In: Current Pharmaceutical Design, Vol. 12, No. 8, 2006, p. 903-23.

Research output: Contribution to journalArticle

TY - JOUR

T1 - From the design to the clinical application of thromboxane modulators

AU - Dogné, Jean-Michel

AU - Hanson, Julien

AU - de Leval, Xavier

AU - Pratico, Domenico

AU - Pace-Asciak, Cecil R

AU - Drion, Pierre

AU - Pirotte, Bernard

AU - Ruan, Ke-He

PY - 2006

Y1 - 2006

N2 - Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.

AB - Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.

KW - Animals

KW - Atherosclerosis

KW - Blood Platelets

KW - Diabetic Retinopathy

KW - Drug Design

KW - Enzyme Inhibitors

KW - Humans

KW - Myocardial Infarction

KW - Neoplasms

KW - Neovascularization, Pathologic

KW - Platelet Aggregation

KW - Prostaglandins

KW - Receptors, Thromboxane A2, Prostaglandin H2

KW - Structure-Activity Relationship

KW - Sulfonamides

KW - Thromboxane A2

KW - Thromboxane-A Synthase

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VL - 12

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JO - Current Pharmaceutical Design

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SN - 1381-6128

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ER -

Dogné J-M, Hanson J, de Leval X, Pratico D, Pace-Asciak CR, Drion P et al. From the design to the clinical application of thromboxane modulators. Current Pharmaceutical Design. 2006;12(8):903-23.