Lead optimization, integrated approaches

This chapter will describe safety lead optimization strategic approaches for small molecules, including commonly used tools and data integration approaches to inform decision-making. 

Fig. 2.1 Lead discovery requires an integrated approach to address a multiple response surface optimization problem properties related to pharmacokinetics, toxicology and pharmacodynamics require optimization for novel chemotypes. The increased difficulty of finding such optima is suggested by darker backgrounds. Modified from [4] with permission.

These presented examples of quantitative descriptions of protein-ligand interactions remain to be a very promising area to address affinity and the selectivity challenge in the future. Those approaches are collectively seen as interesting for a more integrated lead optimization on a simultaneous consideration of numerous balanced descriptors and models for optimization. 

An integrated approach to the use of ADME studies in conjunction with extensive toxicity testing of PBO has been crucial for the development of an optimal regulatory position for the compound. The toxieokinetic studies explain how PBO is metabolized by the body, and how this process in turn leads to its efficacy as synergist for insecticides and also to its activity as a mixed function oxidase inducer in mammals. The latter property accounts for the principal toxicological hndings seen with the compound, namely liver tumours in mice and weak thyroid effects in rats. 

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