A Unified Approach to Lead-Oriented Synthesis


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.

[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.

Hosted By

The European Laboratory Research & Innovation Group Our Vision : To provide outstanding, leading edge knowledge to the life sciences community on an open access basis
Event Logo Follow us on Twitter

Get the App

Get this event information on your mobile by
going to the appstore or google play and search for 'elrig'
Eventflo Home
copyright ELRIG,, Labhoo Ltd 2003-2021