New Developments on Thromboxane and Prostacyclin Modulators Part I: Thromboxane Modulators

Abstract

The pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases can be related to arachidonic acid (AA) metabolites. 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 degradation of AA by the cyclooxygenases. TXA(2) is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction. It is involved in a series of major pathophysiological states such as asthma, myocardial ischemia, pulmonary hypertension, and thromboembolic disorders. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by several pharmaceutical companies since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. Moreover, the recent literature reported the interest of thromboxane modulators, which combine another pharmacological activity such as, platelet activating factor antagonism, angiotensin II antagonism, or 5-lipoxygenase inhibition. In this review, we will propose a description of the recently described thromboxane modulators of major interest from both a pharmacological and a chemical point of view.

Use of hypothermia in the intensive care unit

“…TTM decrease the extravasation of hemoglobin following TBI [34] . Following IR injury or trauma, regional production of endothelin (ET-1), thromboxane A2 (TxA2) and prostaglandin I2 (PGI2), become altered, affecting endothelium [130,131] . ET and TxA2 act as vasoconstrictors, and PGI2 as a vasodilator.…”

Spinach Saponin-Enriched Fraction Inhibits Platelet Aggregation in cAMP- and cGMP-Dependent Manner by Decreasing TXA2Production and Blood Coagulation

“…TXA 2 receptor antagonist sulotroban (Stegmeier et al, 1984), TXA 2 synthase inhibitor furegrelate (Gorman et al, 1983), and drugs combining the properties of both TXA 2 receptor antagonist and TXA 2 synthase inhibitor (i. e. ridogrel and terbogrel) have been developed. Dual compounds proved to be more interesting in therapeutics and promising anti-thrombotic agents (Dogné et al, 2004;Hanson et al, 2005).…”

Human thromboxane synthase: comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel

“…TXA 2 is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction. Recent studies have also pointed out TXA 2 as a significant stimulatory molecule in the proliferation of vascular smooth muscle cells, mitogenesis accelerating hemostasis and in the proliferative response to vascular injury [5][6][7] . Arachidonic acid, the 20 carbon unsaturated fatty acid precursor of TXA 2 , is cleaved from membrane phospholipids by phospholipase A2 (PLA 2 ).…”

“…The last step in TXA 2 biosynthesis is the conversion of PGH 2 to TXA 2 by TXAS, and the production of 12-L-hydroxy-5,8,10-heptadecatrienoic acid and malondialdehyde 1,4 . The biological activities of TXA 2 are related to a series of pathologic conditions including thrombosis and thrombotic disorders 1,4,5,7,8 , asthma 1,4,9 , myocardial infarction, unstable angina, atherosclerosis, Trypanosoma cruzi infection (Chagas disease) and cancer [10][11][12] . Several TXA 2 modulators have been described over the last decades 6,[13][14][15] .…”