Target compound profile

Table 3.1 Dependence of the target compound profile (TCP) on minimum solubility at neutral pH for an oral agent.

These so-called Pareto-based techniques do not force consolidation over multiple criteria in advance and aim to return a representation of the set of optimal compounds. They support discussion between team members who may have different views on the downstream impacts of different risk factors perhaps, for example, one team member may know that there is a reliable biomarker for one potential side-effect. This would then mean that assessing this risk need not consume much development time and cost, and the risk factor can have a reduced weighting within the target product profile being evolved by the team. 

In this chapter, the full BioPrint approach is described, as available from Cerep in terms of both the data set and the ability to have new compounds profiled and the results provided in the context of the BioPrint data set, including the known in vivo side effects of near neighbors in this biological space (see Section 2.5). The results for the differentiation of hit/lead compounds (see Section 2.3.2.1) sometimes use a subset of the 70-100 pharmacological assays that provide the maximum signal. Usually a decision on future work prioritization could be clearly made from the data from these subsets, saving time and money. For key reference/tool compounds, a full profile was used and is recommended to be used, as unexpected off-target activities may be found that cannot usually be predicted. 

Tab. 9.2 Target class profile for WOM BAT.2004.1. Numbers in the Compounds column indicate the number of structures active at least once per each target, and the percentage from the total number of entries is given in the rightmost column...

We also plan to perform bioassays on synthetic intermediates and target compounds to allow for development of a preliminary structure-activity profile for these novel herbicides. 

When one uses a dissimilarity threshold of 0.4 for the neighbors (i.e. the least stringent threshold), the profile can be predicted for 90% of the 300 diverse target compounds only 10% were labeled as non-predictable . 

By using this targeted approach, one can limit compound-profiling activities to areas of high likelihood of BMT and optimize the cost-effectiveness of such screening. 

When a major target compound and a minor impurity is to be separated, the minor component will have little or no effect at all on the band profile of the major component. The band profile of the minor impurity, however, is strongly affected by the presence of the major component. 

On the other hand, the SIM analysis of a predefined set of analytes (Fig. 3.1.4a) require visual inspection, but only to exclude unexpected interferences in the signal of a target compound. For the purpose of detecting unexpected interferences, it is necessary, and is also a CAP accreditation requirement, to monitor at least two ion species per compound (Fig. 3.1.4b and c), so as to recognize artificial variations in the intensity ratios between two ion chromatograms. Figure 3.1.5 shows examples of characteristic organic acid profiles in patients with selected conditions [32]. 

While the attributes of a drug-like profile are in no way to be minimized, the first and foremost properties for a proposed test series during early drug discovery is certainly their assay-likable profile - that is, if it cannot be tested you will not get a result, or even worse, one may perceive that one has an inactive compound and thus erroneously derive a negative SAR data point. Indeed, for the case of esmolol, the entire discovery process was almost halted when its first two series of target compounds were either too insoluble or too plagued by ISA, to be able to be effectively screened. 

Figures 2a and 2b allow to observe pressure effect on the total permeation. It is possible to see as higher as vacuum better the total permeation, but separation capability is reduced as shown in Figure 2b and confirmed by selectivity profile in Figure 3a. A recovery (%) is presented in Figure 3b, concentration increases of the target compound in feed provides lower recovery results. This is an interesting graph for process set up definitions.

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