Discussion

The 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.[1] 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.

[1]Angew. Chem. Int. Ed. 2012, 5, 1114–1122.