Metabolic stability brain penetration

The issues chemists deal with during lead optimization are the same that contribute to general drug-likeness the need to reduce toxicity or to improve solubility, oral absorption, blood-brain barrier penetration and metabolic stability. Computational methods that can directly predict these properties of compounds would allow for the design of high-speed chemistry libraries which are instrumental in solving these specific needs. 

Tissue treatment volumes of the substance being infused are a strong function of the tissue elimination half-life, which reflects the sum of both metabolic and micro vascular tissue clearances. Table 9.2 summarizes how this treatment volume and associated penetration distance varies with the characteristic tissue elimination half-life of the infused species. Various elimination half-lives were used for these simulations and an infusion rate of 3 pL/min into brain for 12 hours was assumed. For the extreme case of a macromolecule undergoing no metabolism, the treatment volume is 27 cm, with a penetration distance of 1.9 cm. For a more realistic tissue elimination half-life, as might be encountered with weakly binding monoclonal antibodies or stabilized analogs of somatostatin or enkephalin peptides, this volume and the distance, respectively, decrease only to 14 cm and 1.5 cm. 

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