Tool compounds

This low viscosity resin permits cure at low (70°C) temperatures and rapidly develops excellent elevated temperature properties. Used to increase heat resistance and cure speed of bisphenol A epoxy resins, it has utihty in such diverse appHcations as adhesives, tooling compounds, and laminating systems. A moleculady distilled version is used as a binder for soHd propellants (see Explosives and propellants) and for military flares (see Pyrotechnics). Its chief uses depend on properties of low viscosity and low temperature reactivity, particularly with carboxy-terminated mbbers. 

SP-600125 was one of the first JNK inhibitors to be reported with potent JNK 1, 2 and 3 inhibitory activity (IC50 = 40,40 and 90 nM, respectively) [37], This tool compound has been studied extensively in a variety of cellular and animal models of inflammation and neuroprotection, among others. The profile of SP-600125 has been discussed in a number of reviews [6,28,29] and will not be discussed here. 

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. 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

The pre-clinical drug discovery process is typically a sequential selection and optimization process focusing, as summarized in Table 2, on different essential properties at each step. " Tool compounds required for early in vitro or in vivo target validation typically do not need to satisfy the same stringent in vivo efficacy and safety criteria as clinical candidates and drugs, which again depend on the targeted therapeutic indication. ... 

Non-selective PKB inhibitors have been extensively used as tool compounds to elucidate the role of this kinase in the biology of human cancers. Thus, PKB isoforms are potently inhibited by promiscuous kinase inhibitors like staurosporine (compound 22, Fig. 5 IC50 = 48 to 11 nM for PKBa) [131-133] and derivatives thereof (e.g., compound 23, Fig. 5) [134]. Another example of a potent and non-selective pan-PKB inhibitor is Ro-31-8220 (compound 24, Fig. 5), a PKC inhibitor (IC50 = 10 nM) [135] that also interferes with PKB kinase activity (IC50 = 240 nM for PKBa). 

Table 2 Peptidic opioid receptor tool compounds.

Figure 1 Non-peptidic tool compounds for the 5 opioid receptor (antagonists).

In conclusion, the investigation of peptidic and non-peptidic tool compounds for the 5 receptor have demonstrated the potential use of 5 agonists and antagonists for a variety of clinical applications, especially for the treatment of pain. Full exploitation of this potential will however only be possible with ideal non-peptidic compounds having high potency, selectivity and, above all, optimal drug metabolism and pharmacodynamic characteristics. 

PBPs). A group at Lilly has introduced the radiolabeled probe 56 and fluorescence-labeled probe 57 as tool compounds to profile the PBPs in different bacterial strains using SDS-PAGE (Fig. 26) [100, 101]. At this time, no MS analysis of the protein bands has been performed. 

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