ADME criteria

The hierarchical model is closest to the traditional approach and meets the needs of a focused, disciplined approach, where molecules are drug-like, with a real possibility of passing some of the ADME criteria. The horizontal model is optimum for looking for exceptions to drug-like property rules and can build SAR streams much... 

Figure 6.2. Strategies for the design of decision trees for new compound evaluation. ADME-based screens can be incorporated in many places in a decision tree, three examples are illustrated A, ADME screens are run as a panel in parallel with early activity screens, compounds proceed to further biological screens after meeting set criteria B, ADME screens are run after a compound meets set potency criteria and compounds proceed to further biological screens after meeting set ADME criteria C, critical ADME screen (metabolic stability in this case) is run on compounds that meet potency criteria and then full ADME screen panel is run before compounds proceed.

In a recent classification study, scaffolds taken from natural products were subjected to a two-step analysis in order to identify a diverse set of natural product scaffolds with preferred ADME-properties." Molecular diversity analysis and selection of natural product scaffolds were carried out using cell-based partitioning and the BCUT metrics." To approximate ADME parameters, rule-of-five " calculations were carried out. A set of about 50 natural product scaffolds fulfilled the desired diversity and ADME criteria. ... 

A multiplicative scheme provides greater flexibility to reflect the relative importance of the individual properties, in particular if there are critical aiteria that must be achieved. In a multiplicative scheme, a failure to meet a critical criterion will result in a very low, or even zero, desirability index, which will result in the compound being killed. For example, if a compound has no potency against the therapeutic target, it will not usually be of interest even if the ADME properties are ideal. However, when interpreting the results it is important to note that, in a multiplicative scheme, the overall desirability index will decrease exponentially with the number of Mlures, therefore a compound that fails multiple low-importance criteria may receive the same desirability index as a compound that is perfect except for a moderate outcome for a single critical criterion. Qualitatively, it may be easier to fix a compound with one poor property than to solve multiple minor issues simultaneously. An additive scheme can help with this interpretation, because the desirability index will decrease linearly with the number of failures. ... 

Figure 15.5 Scoring profile for selection of compounds intended for an orally administered drug against a peripheral target, based on predicted ADME and physicochemical properties. A desired criterion is defined for...

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