Thromboxane Receptors Antagonists And/Or Synthase Inhibitors

Thromboxane Receptors Antagonists and/or Synthase Inhibitors Giovanni Davı`, Francesca Santilli, and Natale Vazzana Contents 1 Introduction .................................................................................. 262 2 TP Receptors and Their Antagonism ....................................................... 263 2.1 Molecular and Cellular Biology ...................................................... 263 2.2 TP Receptor Signaling in Platelets ................................................... 265 2.3 TP Receptor Signaling in Vascular Endothelial and Smooth Muscle Cells ............................................................. 267 3 Drugs Affecting TXA2 Action: Other than COX Inhibitors ............................... 267 3.1 Inhibitors of Thromboxane Synthase ................................................. 267 3.2 Dual TXS Inhibition/TP Antagonism ................................................ 268 4 Dual COXIB/TP Antagonists: A Possible New Twist in NSAID Pharmacology and Cardiovascular Risk ......................................................................... 270 4.1 TP Antagonists ........................................................................ 271 5 Pathophysiological Rationale for the Superiority of TP-Receptor Antagonists Over Aspirin ....................................................................................... 272 5.1 Advantages as an Antithrombotic Agent ............................................. 272 5.2 Relevance of TP Receptors Inhibition in Atherosclerotic Disease .................. 274 5.3 Ischemic Stroke: The Reasons of a Choice .......................................... 275 6 Great Expectations Disappointed: Did Terutroban Fail to Perform, or PERFORM Did Fail? .................................................. 276 6.1 Preliminary Data Revisited ........................................................... 276 6.2 The PERFORM Design Revisited .................................................... 278 7 Future Perspectives .......................................................................... 279 8 Conclusions and Implications for Clinical Usefulness of TP Antagonists ........................................................................... 280 References ....................................................................................... 282 G. Davı` (*) • F. Santilli • N. Vazzana Internal Medicine, University of Chieti, Chieti, Italy e-mail: [email protected] P. Gresele et al. (eds.), Antiplatelet Agents, Handbook of Experimental 261 Pharmacology 210, DOI 10.1007/978-3-642-29423-5_11, # Springer-Verlag Berlin Heidelberg 2012 262 G. Davı` et al. Abstract Atherothrombosis is the major cause of mortality and morbidity in Western countries. Several clinical conditions are characterized by increased inci- dence of cardiovascular events and enhanced thromboxane (TX)-dependent platelet activation. Enhanced TX generation may be explained by mechanisms relatively insensitive to aspirin. More potent drugs possibly overcoming aspirin efficacy may be desirable. Thromboxane synthase inhibitors (TXSI) and thromboxane receptor antagonists (TXRA) have the potential to prove more effective than aspirin due to their different mechanism of action along the pathway of TXA2. TXSI prevent the conversion of PGH2 to TXA2, reducing TXA2 synthesis mainly in platelets, whereas TXRA block the downstream consequences of TXA2 receptors (TP) activation. TXA2 is a potent inducer of platelet activation through its interaction with TP on platelets. TP are activated not only by TXA2, but also by prostaglandin (PG) D2, PGE2, PGF2a, PGH2, PG endoperoxides (i.e., 20-HETE), and isoprostanes, all representing aspirin-insensitive mechanisms of TP activation. Moreover, TP are also expressed on several cell types such as macrophages or monocytes, and vascular endothelial cells, and exert antiatherosclerotic, antivasoconstrictive, and antithrombotic effects, depending on the cellular target. Thus, targeting TP receptor, a common downstream pathway for both platelet and extraplatelet TXA2 as well as for endoperoxides and isoprostanes, may be a useful antiatherosclerotic and a more powerful antithrombotic intervention in clinical settings, such as diabetes mellitus, characterized by persistently enhanced thromboxane (TX)-dependent platelet activation through isoprostane formation and low-grade inflammation, leading to extraplatelet sources of TXA2. Among TXRA, terutroban is an orally active drug in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. Despite great expectations on this drug supported by a large body of preclinical and clinical evidence and pathophysiological rationale, the PERFORM trial failed to demonstrate the superiority of terutroban over aspirin in secondary prevention of cerebrovascular and cardiovascular events among ~20,000 patients with stroke. However, the clinical setting and the design of the study in which the drug has been challenged may explain, at least in part, this unexpected finding. Drugs with dual action, such as dual TXS inhibitors/TP antagonist and dual COXIB/TP antagonists are currently in clinical development. The theoretical rationale for their benefit and the ongoing clinical studies are herein discussed. Keywords Antiplatelet therapy • Atherothrombosis • Ischemic stroke • Platelet activation • Thromboxane biosynthesis • TP antagonists 1 Introduction Atherosclerosis and its clinical manifestations (i.e., ischemic heart disease, cerebrovascular or peripheral artery disease) are major causes of mortality and morbidity in Western countries. Thromboxane Receptors Antagonists and/or Synthase Inhibitors 263 Conventional antiplatelet agents such as aspirin or clopidogrel are currently used in the prevention of cardiovascular events. However, more effective drugs with less bleeding or gastrointestinal complications are desirable. Thromboxane (TX) A2 is involved in a diverse range of physiological and pathophysiological processes, including thrombosis, asthma, myocardial infarction (MI), inflammation, acquired immunity, and atherogenesis. Thus, the stimulation of TX/endoperoxide receptors (TP) elicits diverse biological effects under both nor- mal and pathological conditions. Stimulation of TP results in activation of different signaling cascades that regulate the cytoskeleton, cell adhesion, motility, nuclear transcription factors, proliferation, cell survival, and apoptosis (Nakahata 2008). TXA2 is the major product of the arachidonic acid (AA) metabolism in platelets that, in response to various stimuli, is produced via the consequent actions of cyclooxygenase (COX) and TX synthase (TXS). Through its interaction with TP receptors on platelets, TXA2 is a potent inducer of platelet activation (Davı` and Patrono 2007). Furthermore, the activation of endothelial TP promotes the expression of adhesion molecules and favors adhesion and infiltration of monocytes/macrophages. TP receptors exhibit a wide distribution within the cardiovascular system; in fact, these receptors are membrane-bound G protein-coupled receptors (GPCR) found not only on platelets but also on circulating inflammatory cells, such as macrophages or monocytes, and in vascular endothelial cells, and smooth muscle cells (Meja et al. 1997; Miggin and Kinsella 1998). Thus, antagonists of TP may have some advantages over aspirin as they not only block the effect of TXA2 on platelets, but also inhibit other ligands such as prostaglandin (PG) endoperoxides and isoprostanes. Because of the wide distribution of TP receptors in platelets, in the vascular wall or in atherosclerotic plaques, TP antagonists inhibit also the effects of TXA2 over TP receptors on vascular cells or in the plaque. Therefore, antagonists of TP receptors may not only have antiplatelet effects but also impact endothelial dysfunction and the inflammatory component of atherosclerosis (Chamorro 2009). 2 TP Receptors and Their Antagonism 2.1 Molecular and Cellular Biology TP receptor is highly distributed in various tissues. In addition to platelets, endothelial cells, smooth muscle cells, glomerular mesangial cells, cardiac myocytes, and many other cells express the TP receptor (Fig. 1) (Nakahata 2008). The multiple cellular signaling and regulatory mechanisms activated through TP have been only recently characterized. In particular, it has been reported that reactive oxidant species (ROS)-dependent upregulation of TP expression may increase TXA2/isoprostane responses. This mechanism may significantly contribute 264 G. Davı` et al. TXA2 TP receptor Physiological Response Platelets Endothelial cells Smooth muscle cells Kidney Monocytes/Macrophages Cancer cells Shape change Adhesion molecules Vascular tone Cell proliferation Adhesion molecules Angiogenesis Aggregation PGI2 Proliferation Fibrosis Infiltration Metastatization Secretion Angiogenesis Bronchoconstriction Glomerulosclerosis Fig. 1 TP receptor expression and functions. The thromboxane (TX) A2 receptor (TP) is expressed in a variety of tissues and cells such as platelets, endothelial cells, vascular and bronchial smooth muscle cells, kidney, monocyte/macrophages, and cancer cells. TP activation in these cells is critically involved in the pathobiology of a wide range of diseases, including atherothrombosis, hypertension, renal disease, immune/inflammatory disease, and cancerogenesis. Abbreviations: PGI2 prostacyclin to platelet activation and atherothrombosis in several clinical setting associated with enhanced oxidative stress, such as hypercholesterolemia,

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