Brain, lipophilicity optimum

Though there are no drugs yet on the market from this particular system, the pyridine-pyridinium redox CDS has been widely exploited experimentally to deliver hormones and drugs to the brain (Bodor and Farag, 1984 Shek ef al., 1987). By using a variety of groups, R, in 27 from, for example, methyl through to octyl, the lipophilicity can be adjusted to provide optimum properties for passive transport. 

The concept of optimum lipophilicity of a drug for passive transport, e.g. gastrointestinal absorption or transfer through the blood-brain barrier. Nowadays many medicinal chemists are famihar with these relationships and do not any longer realize that much of our knowledge came from such analyses. 

As stated earlier, prediction is not the main goal of a QSAR analysis. Much more often general conclusions on the reduction of toxic properties, on selectivity, on optimum lipophilicity to pass the blood-brain barrier or, on the other hand, to avoid CNS side effects, are more important for the optimization of a lead structure. As it still is industrial praxis (and will remain for patent reasons) to synthesize and test large numbers of closely related analogs, QSAR is also an important tool to decide when to stop a synthetic program (compare e.g. eqs. 178, 179 chapter 7.4) [786, 1095]. 

Thus, the conclusions from equation (27) are that the two activities cannot be separated, but for optimum hypotensive activity the lipophilicity of the compounds should be around 1.5. Such analogs can readily cross the blood-brain barrier and their central effect will override the peripheral effect. All other attempts to find chemically related analogs with improved selectivity must fail. Thus, no more syntheses and testing of compounds within this series need to be performed. Several other examples are known where desired activities have been compared with toxicides, especially for antitumor drugs. In some cases the syntheses of further analogs were stopped because no better therapeutic indices could be expected. " ... 

---