Poster
27

A Unified Approach to Lead-Oriented Synthesis

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
[1]. S. M. Paul, D. S. Mytelka, C. T. Dunwiddie, C. C. Persinger, B. H. Munos, S. R. Lindborg, A. L. Schacht, Nat. Rev. Drug Discov. 2010, 9, 203-214.
[2]. A. Nadin, C. Hattotuwagama, I. Churcher, Angew. Chem. Int. Ed. 2012, 51, 1114-1122.
[3]. F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752-6756.
[4]. A. H. Lipkus, Q. Yuan, K. A. Lucas, S. A. Funk, W. F. Bartelt, R. J. Schenck, A. J. Trippe, J. Org. Chem. 2008, 73, 4443-4451.
[5]. P. Tosatti, J. Horn, A. J. Campbell, D. House, A. Nelson, S. P. Marsden, Adv. Synth. Catal. 2010, 352, 3153–3157.

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