From fungus to pharmaceuticals – the chemistry of statins

It has long been recognised that high circulating levels of cholesterol are associated with the development of cardiovascular disease. With the discovery of the cholesterol biosynthetic pathway in 1950, it was soon realised that blockade of key conversions in this pathway may provide useful therapeutic targets for the management of hypercholesterolaemia. In the 1970s the first useful inhibitors of cholesterol biosynthesis were isolated, and paved the way for what would become a multimillion dollar pharmaceutical industry. Modern-day statins are incredibly effective hypolipidaemic agents, interrupting cholesterol biosynthesis at the rate-limiting step through a competitive inhibition mechanism. These compounds’ structures interact with key amino acid residues through a variety of defined bonding interactions, and by understanding how these interactions form, better, and safer, hypolipidaemic agents were found. This review describes the historical development of statins and brings us up-to-date with current structure-activity relationships between statins and their target enzyme.