Lead optimisation

During the later stages of development and lead optimisation, other factors (such as how the drug metabolises) are taken in to account. Additionally, any impurities and intermediates are considered and structures are modified to 

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Further lead optimisation chemistry (aided by structure) <... 

Furness,L.M. Expression Databases for Pharmaceutical Lead Optimisation. Proceedings of the 13 Noordwijkerhout-Ca-merino Symposium [2001], Trends in Drug Research III. Pharmacochemistry Library, volume 32 Ed. H. van der Goot (Elsevier). 

However, adoption would require the acceptance of a different strategy for lead discovery and possibly also lead optimisation. The key changes required would be that beyond the high-throughput screen-... 

This basic chemistry generator system has proved itself to be adept at producing a diverse range of chemistry (e.g. Garcia-Egido et al. 2002, 2003). However, it is more effective operation as a lead optimising device if certain tasks can be off-loaded to two sister machines which act in concert with the main device. These are similar in their configuration to the main machine but are adapted to achieve their specific roles. Thus a reaction validation and optimisation platform (VOP Fig. 4) takes this role offline. 

Solid-phase synthesis for small organic compounds is widely used in research and academia for rapid lead finding and lead optimisation. The... 

Weaver DC. Applying data mining techniques to hbrary design, lead generation and lead optimisation. Curr Opin Chem Biol 2004 8 264-70. 

There is an increasing focus on trying to select more easily developable molecules at an early stage, so that the chance of failure at the very expensive later phases is minimised. Pharmaceutical companies therefore decide on which properties of a new molecule are key to faster development, for example, selection of soluble compounds to facilitate formulation. Amongst these is the selection of molecules with low or acceptable toxicity. Thus, a company may decide to develop high-throughput in vitro screens for cytotoxicity for use at the lead optimisation stage. 

Ronzoni, S., Peretto, I., Giardina, G.A.M. Lead generation and lead optimisation approaches in the discovery of selective, non-peptide ORL-1 receptor agonists and antagonists, Exp. Opin. Ther. Patents 2001, 11, 525-546. 

Lead optimisation is the synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness (IUPAC). This phase begins with the first chemical lead or lead series selected for optimisation (i.e. the "lead series selected" milestone) and concludes with a decision for an optimized compound to enter preclinical development (i.e. the "pre-clinical candidate selected" milestone). This phase consists of testing of a compound to determine the chemical structure that has the optimum potency and selectivity for the target in question. The phase includes the search for backup compounds and may also include early ADME and toxicity evaluation. 

Hit rates from HTS are often low and the hits obtained fail to progress into lead optimisation HTS is the predominant technique for hit finding employed by the majority of pharmaceutical companies and is central to modern drug discovery. However, many scientists are now regarding HTS as a costly necessity rather than a method of choice.191... 

Bos M, Sleight AJ, Godel T, Martin JR, Riemer C, Stadler H. 5-HT6 receptor antagonists lead optimisation and biological evaluation of V-aryl and. Y-hctcroaryl 4-amino-benzene sulfonamides. Eur J Med Chem 2001 36 165-178. 

Selway et al. [13] have employed a selection of other chemistries in addition to acylation, notably sulphonylation, alkylation and aryl coupling, using boronic acid in the generation of solution-phase arrays in lead optimisation work. 

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