Hit triage

Hit Triage Medicinal Chemistry Strategies to Improve the Odds of Success in Discovery... 

The potential sources of the compounds that are evaluated in a hit triage process are described in other chapters in this volume. These sources may include a high throughput screen (HTS) of a diverse compound collection, a targeted screen of... 

Fig. 1 Different sources of hits typically provide different distributions of number of hit compounds and amount known (and relevant) about those compounds, each of which contributes to the decision making process of hit selection and hit triage...

Fig. 2 Hit triage decision making requires inputs of experimental and calculated data and medicinal chemistry experience and expertise to arrive at an assessment of the probability of advancing individual chemical series...

HTS data and secondary screening for hit validation and determination of kinetic on/off rates. These data have been successfully incorporated into hit triage by enhancing the understanding of SAR differences between potential scaffolds [24]. In this example, those differences allowed informed decision making in the choice of which series to pursue and which to deprioritize. 

Because the goal of hit triage is to identify chemical series that hold promise for further optimization, an approach to characterize the ADME properties of a series, not just individual compounds is often useful. Where possible, characterizing the structure-ADME property relationship, in much the same way that a structure-potency relationship is defined, can be valuable for assessing the probability that a given structural series can be successfully optimized. The goals of this ADME property characterization are twofold (1) to identify specific structural features that may be liabilities (benefits), and (2) to identify general structure-ADME property correlations. 

From an early drug discovery and hit triage perspective, a simplification that is typically made is to focus initially on CYP metabolism that occurs in the fiver. This simplification is appropriate for the majority of compounds - some compounds will be cleared by other mechanisms, but it is generally assumed that they must be relatively stable to CYP metabolism to achieve a desirable PK profile. 

The trend toward decreased stability of compounds with increased lipophilicity and MW is obvious. This analysis can provide information about the roles of these two properties in contributing to clearance for this series. Again, the important question for hit triage decision making is how the hypothesized structure-clearance trends correlate to the property trends for other relevant biological properties. 

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

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