Chapter 4: Lead- and Fragment-oriented Synthesis

Due to the high attrition rates in drug discovery, the consideration of the molecular properties of screening compounds has become paramount to the pharmaceutical industry. Hence, over the past 20 years, lead- and fragment-based approaches to hit identification have been developed and refined. As guidelines for the molecular and structural properties of leads and fragments have developed, it was realised that dedicated research into the generation of ‘lead-like’ and ‘fragment-like’ compounds was needed to enhance lead-like and fragment screening libraries. This reviews details the drivers, definitions and progress in the implementation of lead- and fragment-oriented synthesis. The strategies employed, as well as the synthetic and analytical methodologies developed are outlined and discussed.