Lead-oriented synthesis (LOS) towards diverse molecular scaffolds


The high attrition rate (∼97%) of drug candidates within the discovery pipeline has been attributed to poorly defined chemical properties for lead compounds. The lead optimisation process is associated with inevitable increases in both the molecular weight and lipophilicity of lead molecules. To reduce attrition, ideal 'lead-like' properties were defined by Churcher to allow greater flexibility for the optimisation of leads into drugs.[1] However, the development of synthetic methodologies with the potential to systematically target lead-like chemical space, or 'lead-oriented synthesis' (LOS), remains a largely unmet challenge.

This poster describes a bespoke computational tool which has been used to identify a valuable connective reaction for LOS; the allylation of amino acid esters to give quaternary amino ester building blocks. The same tool directed a synthetic programme to prepare diverse, novel scaffolds from these allylated building blocks. Methodologies (iodine-mediated cyclisations; ring-closing metathesis; lactamisations; hydantoin formations; Heck reactions) were developed based on their ability to generate molecules that retain their lead-like properties after decoration, giving access to new areas of chemical space.

[1] Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem. Int. Ed. 2012 , 51, 1114.

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