Results of a phase II clinical trial of a novel oral thrombin receptor antagonist (TRA) were published in the March 14th issue of The Lancet.
SCH 530348 met the study’s primary endpoints of safety and tolerability, and caused no increase in major and minor Thrombolysis in Myocardial Infarction (TIMI)-scale bleeding when given with current standard antiplatelet therapy (aspirin and clopidogrel) for patients undergoing percutaneous coronary intervention (PCI), commonly known as balloon angioplasty, with stenting. Thrombin is a protein with key roles in blood coagulation – as well as activating platelets for aggregation, thrombin is involved in the production of fibrin, a fibrous protein involved in blood clotting and wound healing. Patients with blocked coronary arteries undergoing PCI are at risk of blood clots and are usually treated with anti-clotting drugs such as aspirin or clopidgrel. Although these drugs are effective at preventing blood clots, they increase the risk of bleeding and there is a need for safer drugs to prevent clots during PCI.
The new study, which involved over 1000 patients, was designed to evaluate the safety and efficacy of SCH 530348 in patients undergoing PCI. SCH-530348 acts as an antagonist at the thrombin receptor and reduces thrombin-induced platelet activation but doesn’t interfere with thrombin’s role in fibrin synthesis. Compared to standard-of-care treatment alone, addition of SCH 530348 led to much greater inhibition of thrombin-receptor agonist peptide (TRAP)-induced platelet aggregation in both loading and maintenance doses.
SCH 530348 is related to the natural product, himbacine, and has a complex structure with seven stereogenic centres but can be synthesised efficiently using a diastereoselective intramolecular Diels-Alder reaction which generates the core tricyclic structure. SCH 530348 is being developed by Schering-Plough for the prevention and treatment of atherothrombotic events in patients with acute coronary syndrome and in those with prior myocardial infarction or stroke, as well as in patients with existing peripheral arterial disease. SCH 530348 is currently being evaluated in two large-scale multinational, randomized, double-blind, placebo-controlled Phase III clinical trials.
Cardiac hypertrophy is a thickening of the heart muscle – characterized by increased cell size rather than number – in response to conditions such as high blood pressure and coronary heart disease, which results in a decrease in size of the chambers of the heart, including the left and right ventricles. Since hypertrophy is associated with heart failure, irregular heart rhythms and an increased risk of angina and heart attack, understanding the mechanisms underlying this abnormal thickening is of great importance. Scientists at the Babraham Institute have now identified a new signalling process in the heart which contributes to cardiac hypertrophy. Rhythmical Ca2+ increases are fundamental to contraction of the heart muscle, but elevated Ca2+ levels also regulate the gene transcription that leads to hypertrophy. The Babraham team found that it is localised increases in Ca2+ concentrations in the cell nucleus that activate the genes responsible for hypertrophy. These nuclear Ca2+ signals, which are distinct from the Ca2+ signals that control the rhythmical contractions of the heart, were found to be generated by opening of the inositol 1,4,5-trisphosphate (IP3) receptor calcium channels (IP3Rs) which surround the nucleus.
These channels open in response to the increased cellular levels of IP3 that are generated on binding of the vasoconstricting peptide, endothelin-1, to receptors on the surface of cardiac myocytes. Nuclear factor of activated T cells (NFAT), which is known to regulate genes involved in pathological hypertrophy, was shown to be activated by these IP3-mediated increases in nuclear Ca2+ levels and not by the Ca2+ signals associated with contraction. The study confirms the importance of the endothelin pathway in cardiac hypertrophy and provides evidence that modulation of IP3 signalling would be a suitable target for future therapies.
The study is published in the journal Molecular Cell.
Cardiac hypertrophy, or thickening of the heart muscle, occurs naturally in athletes but may also be a pathological response to high blood pressure or stenosis of the aortic valve. Pathological hypertrophy allows the heart to continue pumping blood against the increased pressure but, over time, can lead to loss of function and heart failure. Researchers at the University of California, Davis, have now identified soluble epoxide hydrolase (sEH) as a key enzyme in the development of angiotensin II (Ang II)-mediated cardiac hypertrophy. sEH hydrolyses the blood pressure-regulating epoxyeicosatrienoic acids (EETs) into dihydroxyeicosatrienoic acids (DHETs), which show reduced biological activity. The study, which is published in the January 13th issue of the Proceedings of the National Academy of Sciences showed that levels of sEH in the heart were elevated in two rodent models of Ang II-induced hypertrophy. The Ang II receptor blocker, losartan, prevented the increase in sEH and administration of an inhibitor of sEH, 1-(1-acetyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS), prevented the pathogenesis of Ang II-induced hypertrophy.
The authors suggest that inhibition of sEH could be a useful approach to treat Ang II-induced cardiac hypertrophy. Existing treatments for heart failure include β-blockers, angiotensin converting enzyme (ACE) inhibitors or Ang II receptor blockers, diuretics and drugs that improve the heart’s ability to pump.
In another study, published in the journal Clinical Science, administration of a different sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was found to reduce kidney damage caused by Ang II-induced hypertension in spontaneously diabetic rats.