Abstract

A Unified Approach to Lead-Oriented Synthesis

Richard Doveston, Researcher, Leeds University

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. These properties provide the potential to focus compound screening collections and allow flexibility through lead-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. The problem is compounded further when other factors such as sp3-character and skeletal diversity are also taken into consideration. This presentation will describe a unified approach to address this challenge. Our strategy utilises single connective reactions together with a toolbox of optimised cyclisation methodologies, ultimately allowing for the synthesis of many 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 is prepared in a minimum number of synthetic operations.