Optimal Pattern for Substitution

Placing a probe atom in each nonequivalent position on a lead does not address the question of the effect of multiple substitution. For example, there is no way to address the effect of substitution in the 5- or 6-position on a benzene ring without at least a disubstituted molecule. Using a single set of probe atoms also has a severe risk because once again all the error of measurement is included in the comparison of the parent compound and a probe compound. As in the Free-Wilson design, it would reduce the risk if at least 

Compound Position 2 Position 3 Position 4 Position 5 Position 6  

If multiple positions appear to be sensitive to substitution, a multiple substitution strategy should be considered. Returning to the example of the N-phenyl succinimides a set of seven compounds can be chosen to represent four of the five positions on the aromatic ring (the sixth position is only represented once in the set). 

Choose the Factors (Parameters) That Are Likely to Be Important 

If optimization is being conduaed in a living organism, the compound s log P should be determined or estimated before any steps are taken in the seleaion of substituents. If an estimate of the optimum value for log P for the 

---