Cardiovascular and Smooth Muscle Pharmacology in the Next Decade

In 2008, half of the 15 best-selling cardio-vascular drugs (those with sales of over $2 billion), the sartans, were developed over 30 years ago. A lipid-lowering drug developed over 40 years ago (fenofibrate) also made it into the top fifteen. Rare are those developed more recently. One example is ezetimibe developed in the 1990s. Drugs acting on cholesterol levels such as fenofi-brate, ezetimibe and the statins represent over a quarter of the top fifteen. There are many reasons behind these figures – the duration of the drug development process from synthesis to marketing, the economics of the pharmaceutical industry that in some markets make it more financially rewarding to copy the others than to innovate, etc. Albeit, looking at these figures, a pessimist would be tempted to say that cardiovascu-lar pharmacologists have shown a certain lack of imagination – an optimist would say that there is a large number of potential targets out there just waiting to be discovered and developed. Frontiers in cardiovascular and smooth muscle pharmacology will focus on such potential targets and concepts, as well as on the new technology and methodology required to investigate them. Classical drug research and development was based on the identification of selective membrane targets such as receptors or ion channels that promote a specific reaction to a given drug in the midst of the chemical cacophony of the receptor or ion channel biophase. The invention by Sir James Black of propranolol, the beta-adrenoreceptor antagonist, in the 1960s, was based on the pioneering work done by himself and others on the development of specific ligands for specific adrenoreceptor types. This drug revolutionized the management of angina pectoris and is one of the most important contributions to clinical pharmacology of the 20th century. In the 1960s Black was also cogitating on other applications of receptor pharmacology. He thought that the histamine antagonists available at that time were analogous to alpha-adrenoreceptor antagonists and that the equivalent of propranolol was needed to block histamine-stimulated acid secretion in the stomach. This lead in the 1970s to the H 2-receptor antagonist programme and cimetidine. Such an approach is still highly relevant today and investigation into the roles of 5-HT2Band 5-HT7 receptors as well as 5-HT3-receptor subunits in the gastrointestinal pharmacology and physiology of 5-HT is of prime importance. Given that there are some 800 G-protein coupled receptors, this classical membrane receptor approach still has a bright future. …