Targeted activation

Let us outline one of our approaches with the following simple example. Suppose we have a dataset of compounds and two experimental biological activities, of which one is a target activity (TA) and the other is an undesirable side effect (USE). Naturally, those with high TA and low USE form the first subclass, those with low TA and high USE the second, and the rest go into the third, intermediate subclass. 

A series of 6-substituted 8,9-dimethoxy-2,3-methylenedioxy-6ff-dibenzo[c,h] [2,6] naphthyridin-5-ones (IX) was synthesized and evaluated for topo I-targeting activity as well as for cytotoxicity against different cell lines by Zhu et al. [53]. From the topo I-mediated DNA cleavage data of these compounds (IX), we developed Eq. 7 (Table 5) ... 

Zhu et al. [55] also synthesized a series of ester/amide derivatives of 2,3-dimethoxy-8,9-methylenedioxy-benzo[z]phenanthridine-12-carboxyhc acid (X) and evaluated their topo I-targeting activity as well as cytotoxicity against different cell lines. Topo I cleavage values are given as REC, the relative ef-... 

Experiments conducted to verify that the output measurement of the assay is reflective of the target activity. Results are compared (where possible) to existing literature parameters such as Kd, Kh Km, or EC50. 

The amount of a signal produced in an assay or screen in the absence of a test substance (2) the signal detected from an assay in the absence of TARGET activity often equivalent to negative control. 

There are many examples of the introduction of fluorine enhancing on-target activity and these only represent a small number. Many more will be exemplified in the remaining sections of this chapter. 

Sm complexes with phosphonate ligands were found to target actively growing bone (i.e., tumors fractures).152 Several 153Sm phosphonate complexes were synthesized and evaluated in... 

The modeler supplies the final (or target) activity aj or fugacity fm, which will be achieved at the end of the reaction path, when = 1. The modeler also specifies... 

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. 

Figure 2.6 Compound target activity distribution ( promiscuity ) for 1388 drugs profiled in BioPrint assay panel (with 50% inhibition at 10pM taken as active), shown as a histogram. The number of active compounds is shown along the y-axis and the number of targets along the x-axis (adapted from ref. [6]).

Figure2.7 Selectivity ( promiscuity ,x-axis) intermsofcompound target activity numbers for 1098 drugs from BioPrint profiled in the BioPrint assay panel (with <1 pM IC50 taken as active), versus clogP (hydrophobicity, y-axis) (adapted from ref. [5]).

Table 17.2 Off-target activities of cyclohexylglycine DPP-4 inhibitors (ICso s, nM).

Table 17.3 Potency and off-target activities of P-methyl phenyl-alanine-based DPP-4 inhibitors (IC50 s, nM).

Table 17.7 Potency and off-target activities of fused triazole derivatives.

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