DiscussionThe concept of lead-oriented synthesis seeks to address the high attrition rate (~97%) of drug candidates within the discovery pipeline. As the lead optimisation process inevitably increases both the molecular weight and lipophilicity of a lead compound, the definition of ideal ‘lead-like’ properties by Churcher et al in 2012 was significant. It provides the potential to focus lead identification together with flexibility through optimisation, thus reducing attrition. However, the development of synthetic methodologies with the potential to systematically target lead-like chemical space (or ‘lead-oriented synthesis’) remains a largely unmet challenge.
This poster describes a bespoke computational tool which has been used to identify a connective reaction of potential value. This same tool was then used to direct a synthetic programme focussed on the preparation of diverse, novel scaffolds that retain their lead-like properties following decoration.
Angew. Chem. Int. Ed. 2012, 5, 1114–1122.