Lead optimization setting

These specific and general data inputs serve as the basis for making judgments on how substantially the structure of the hit compound(s) will need to change as the potency, ADME, and safety properties are concurrently optimized. These judgments form the basis of the lead optimization effort. As such, an important consideration is the selection of compounds to define the boundaries of the structure-ADME relationship of a series. In some cases, the compounds that are selected for defining the ADME relationships will not be the same set of compounds that have the most potent primary pharmacology. 

While clear rules apply to the acceptance criteria for GLP assays,12,14 15 114 little agreement surrounds what should be included in the acceptance criteria for discovery PK (non-GLP) assays. Korfmacher16 published a set of rules for discovery PK assays based on the simple concept that the rules should become more rigorous as one moves from early PK screening (Level I) of many compounds to rapid PK studies for lead compounds (Lead Optimization—Level II), and finally special PK studies for compounds that are likely to be recommended for development (Lead Qualification—Level III). 

This section will provide an overview on ADME models from our group to illustrate our approach for building predictive models on structurally diverse training sets. Datasets for intestinal human absorption and human serum albumin binding are discussed, while models for other relevant ADME properties have also been obtained. Those models, however, do not stand alone but are used in combination with those models tailored for affinity and selectivity in the frame of multidimensional lead optimization. 

Requests typically come from the lead optimization group for a set of compounds to be tested in a number of ADME/Tox assays. These could be according to predefined campaign strategy or selected a la carte. 

A set of molecules that rank high after this process would be synthesized and subject to biological tests, i.e., in vitro enzymatic assay or binding affinity experiments, in order to confirm design rationales. Simultaneously, X-ray co-crystal structures of these ligands in complex with the target are to be determined to further corroborate modeling results. Positive results from such approaches are decisive for selection of next set of compounds for synthesis and the future directions of lead optimization. 

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