Compound selection sequential simplex

Fig. 2.6. Illustration of the sequential simplex process of compound selection (after Darvas 1974, copyright (1974) American Chemical Society).

Since we wished to optimize this series with a minimal expenditure of our synthetic resources, the sequential simplex technique (SSO) was selected (11,12). This strategy is very resource efficient, requiring only n + 1 compounds to start the optimization, where n is the number of physiochemical parameters used to describe the characteristics of a substituent. We selected pi to account for lipophilicity and field (F) and resonance (R) were used to describe the electronic effects of each substituent (14). Verloop s Sterimol parameters (H), minimum van der Waals radius (B] ) and length (L) were selected to describe the size of the substituent. Using cluster analysis, we selected a set of six substituents that cover physiochemical parameter space well (15). These are-listed in Figure 6. 

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