From the design to the clinical application of thromboxane modulators.
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.
Dogné
Jean-Michel
JM
Natural and Synthetic Drug Research Centre, Medicinal Chemistry, University of Liège, Belgium. Jean-Michel.Dogne@ulg.ac.be
Hanson
Julien
J
de Leval
Xavier
X
Pratico
Domenico
D
Pace-Asciak
Cecil R
CR
Drion
Pierre
P
Pirotte
Bernard
B
Ruan
Ke-He
KH
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000517:prevention & control; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010974:Platelet Aggregation / Q000187:drug effects; D011453:Prostaglandins / Q000494:pharmacology* / Q000627:therapeutic use; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013928:Thromboxane A2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D011453:Prostaglandins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase