| Abstract: | The treatment of neoplastic disease with chemotherapeutic cytotoxic drugs has long been associated with profound nausea and vomiting (emesis). This became the most feared side effect of this type of treatment and was so severe that some patients would withdraw from further treatment, thus jeopardising their clinical outcome and possibly life expectancy. The introduction of the 5-HT3 receptor antagonists had a significant impact in this area, offering substantial reductions in emesis, largely through prophylactic treatment. Unfortunately, some forms of emesis were resistant to treatment with these drugs, so the search has continued to identify new chemical entities with a higher level of efficacy and a broader spectrum of activity. Data generated in animals has identified tachykinin NK1 receptors as highly important in the emetic reflex and experimental evidence strongly supports NK1 receptor antagonists as highly efficacious anti-emetic agents, with unparalleled broad spectrum activity. Several novel antagonists have recently entered clinical development and data are emerging to support their anti-emetic activity. This area continues to attract substantial medicinal chemical research effort. Most major pharmaceutical companies are seeking new matter through structural refinement of early leads or discovery of novel compounds from library screening. The scope of chemical lead matter has advanced from early piperidine and quinuclidines to a spectrum of templates that improve expectations for a well-tolerated therapeutic agent. Recent success in combining 5-HT3 and NK1 antagonists in emesis treatment is expected to greatly advance clinical outcomes with newer and safer agents. |
