ANTCARD · Analogues Of Thromboxane For The Treatment Of Cardiovascular Disease

Analogues Of Thromboxane For The Treatment Of Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of death in the developed world. Each year CVDs cause over 4 million deaths in Europe (47% of all deaths) and over 1.9 million deaths in the European Union (40% of all deaths). Since CVDs are the No. 1 cause of death in the EU and worldwide, research in this field has an incomparable high societal impact globally [1]. Platelets (thrombocytes) play an essential role in haemostasis and a critical role in thrombosis and cardiovascular disease [2]. When a blood vessel becomes damaged, platelets rapidly adhere to the newly exposed collagen and become activated, leading to degranulation and release of thromboxane A2 (TxA2), which is hydrolyzed to thromboxane B2 (TxB2) during this process. ADP (adenosine diphosphate) is released from granules and TxA2 can further recruit and activate platelets to the site of injury. Platelet activation also results in an increase in the affinity state of transmembrane receptors (integrin). Integrin activation not only promotes firm platelet adhesion to the newly exposed extracellular matrix but also supports fibrinogen binding to integrin αIIbβ3, resulting in platelet aggregation and thrombus formation. Activation of platelets is therefore crucial for thrombus formation and occlusion of blood vessels upon rupture of atherosclerotic plaques, leading to myocardial infarction or stroke. Due to the important role of platelets in cardiovascular disease, patients at risk of thrombotic events are routinely prescribed anti-platelet drugs that interfere with the amplification of platelet function, such as aspirin (blocks TxA2 synthesis by targeting cyclooxygenase (COX) and therefore all prostanoids) and clopidogrel (targets the ADP receptor P2Y12). Although aspirin is a first line treatment, its usage is associated with undesirable adverse effects [3] such as gastropathies and gastric ulcers (and potential associated bleeding) caused by blocking COX-1-mediated production of gastro-protective prostaglandins. In addition, aspirin resistance is a common clinical problem [4]. For these reasons, there is considerable interest in targeting the TxA2 pathway by other means, in order to avoid the present drawbacks associated with aspirin use. Therapeutic development of COX isoform specific inhibitors is however of no benefit, as COX-1 is involved in both platelet-mediated TxA2 synthesis and gastric prostaglandin synthesis. Moreover, TxA2 receptor (TP receptor) antagonists have been successfully developed but most of the designed compounds failed to pass clinical trials or toxicity studies [5]. In this project, we therefore propose to develop a fundamentally new strategy: we plan to remove TxA2 as it is produced using a humanised antibody-based drug that targets TxA2 itself. Therefore, synthetic work on an analogue of TxA2 via a novel short synthesis for the synthesis of PGF2α [6] has been done. The aim of the project is the synthesis of thromboxanes and their analogues as well as their biological and pharmacological evaluation. Within the reporting period the synthesis of the starting material has been optimised and kinetic studies of the key step, the domino-aldol reaction, have been performed using NMR to achieve reliable results and to get a better understanding of the reaction itself. Introduction of the side chain via the literature known route as well as development of a new route to introduce the lower side chain of the molecule has been investigated. Beside its use for the synthesis of thromboxanes the optimisation and the new introduction of the lower side chain can be used in the synthesis of prostaglandins, which are also a very important class of natural products. Optimisation of the aldol process is therefore of academic and industrial interest, since the so far used route towards prostaglandin based drugs are very long and expensive [7]. The expected final result is the development of new drugs to treat cardiovascular diseases as an alternative to the standard medication like Aspirin or clopidogrel. Therefore, the synthesis of new thromboxane derivatives are necessary, which are still under development. The impact of this project is the synthesis of active thromboxanes via an economical and ecologically friendly process to develop new drugs, which could lead to treatment of cardiovascular diseases. Since cardiovascular diseases occupy the first and the second place in the top ten causes of death worldwide it is beyond doubt that the development of new drug treatments for cardiovascular diseases is extremely important and of a high societal impact for the European Research Area (ERA). In 2012 47% of all deaths in the Europe were caused by cardiovascular diseases. In summary, the project has a very high societal impact, relevant to the ERA and beyond. It could lead to important new approaches to cardiovascular disease which will have a major impact on the pharmaceutical industry as well. Literature: [1] a) Coronary Heart Disease Statistics 2012- A compendium of health statistics, British Heart Foundation Health Promotion Research Group Department of Public Health (ed. Peter Weissberg), University of Oxford, 2012; b) http://www.ehnheart.org/cvd-statistics.html [2] M. H. Kroll, A. Schafer, Blood 1989, 74, 1181–1195. [3] a) B. Schlansky, J. H. Hwan, J. Gastroenterol. 2009, 44, 44–52; b) K. Meijer, S. Schulmann, Semin. Thromb. Hemost. 2008, 34, 762–771. [4] A. A. Divani, N. D. Zantek, A. Borhani-Haghighi, G. H. Rao, Clin Appl Thromb Hemost. 2013, 19, 5–18. [5] H. J. Ting, J. P. Murad, E. V. P. Espinosa, F. T. Khasawneh, Journal of Cardiovascular Pharmacology and Therapeutics 2012, 17, 248–259. [6] a) G. Coulthard, W. Erb, V. K. Aggarwal, Nature 2012, 489, 278–281; b) V. K. Aggarwal, G. Coulthard, W. Erb, International Patent Application No. PCT/GB2013/051532, 2013. [7] E. J. Corey, N. M. Weinshenker, T. K. Schaaf, W. Huber, J. Am. Chem. Soc. 1969, 91, 5675–5677.

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