Discussion

The concept of lead-oriented synthesis seeks to address the high attrition rate (~97%) of drug candidates within the discovery pipeline.[1] 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 . These properties provide the potential to focus lead compound collections and allow flexibility through optimisation, thus reducing attrition.[2] 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. The problem is compounded further when other factors such as sp3-character[3] and skeletal diversity[4] are also taken into consideration.

This poster describes a unified approach to address this challenge. Our strategy utilised a single connective reaction (Ir-catalysed allylic amination[5]) together with a toolbox of six cyclisation methodologies, ultimately allowing for the synthesis of over 50 highly 3-dimensional molecular scaffolds. Crucially, a bespoke computational tool was employed to proactively identify novel target scaffolds that retained lead-like properties after decoration. This was used to direct a highly efficient synthetic programme whereby a scaffold was prepared in, on average, just three synthetic operations.

References
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