Chemical inhibitors, selection

Boilers and steam systems Steel steam lines can be inhibited by the use of a volatile amine-based inhibitor such as ammonia, morpholine or cyclohexylamine introduced with the feedwater. It passes through the boiler and into the steam system, where it neutralizes the acidic conditions in pipework. The inhibitor is chemically consumed and lost by physical means. Film-forming inhibitors such as heterocyclic amines and alkyl sulphonates must be present at levels sufficient to cover the entire steel surface, otherwise localized corrosion will occur on the bare steel. Inhibitor selection must take into account the presence of other materials in the system. Some amine products cause corrosion of copper. If copper is present and at risk of corrosion it can be inhibited by the addition of benzotriazole or tolutriazole at a level appropriate to the system (see also Section 53.3.2). 

Identification of the P450 form(s) responsible for the metabolism of a xenobiotic can be achieved by correlation of the rates of metabolism of the new entity with the rates of metabolism for marker substrates for specific enzymes in different liver specimens with the levels of the different P450 forms (for review see Wrighton et al., 1993b). A typical approach involves the selection of multiple human tissue preparations with high , medium and low levels of the enzymes of interest. The rate of metabolism of the new entity is assessed in these samples and correlation analyses are performed versus the different marker activities. The enzyme with the highest correlation with the metabolism of the new entity is likely to be the principal enzyme involved in its metabolism. Alternatively, or in addition to correlation analyses, the roles of specific enzymes can be analysed by selective immunoinhibition or chemical inhibition of different P450 forms. The use of chemical inhibitors has been reviewed recently (Halpert et al.,... 

The chemical inhibitor component is also normally selected, after a technical review, from a vendor s standard product range, which may contain anywhere from 20 to 40 programs, grouped into half-dozen or more... 

As an aid to chemical inhibitor treatment selection, some inhibitor selection charts are included in Section 8.4.3.5 as Tables 8.3 to 8.10. Also refer to Chapter 5 and especially Tables 5.1 to 5.5. 

Pooled human liver microsomes or individual human liver microsomal samples should be used for experiments designed to examine the effects of CYP-selective chemical inhibitors or selective inhibitory antibodies. 

Chemical inhibitors should be utilized at concentrations that maintain selectivity for a given CYP enzyme with adequate potency. A range of inhibitor concentrations can be used. 

When chemical inhibition experiments are conducted with a relatively metabolically stable drug candidate (one that must be incubated with relatively high concentrations of human liver microsomes for a relatively long time in order to generate quantifiable levels of metabolite), it is important to take into account the metabolic stability of the inhibitors themselves. Lack of metabolic stability makes some compounds poor choices as chemical inhibitors despite their selectivity. For example, coumarin is a selective substrate of CYP2A6 (Km 0.25 to 0.5 pM) (111) and it would be a good selective competitive inhibitor of CYP2A6 if it were not metabolized so rapidly by human liver microsomes. 

Inasmuch as the selectivity of some chemical inhibitors is questionable or even variable depending on the incubation conditions, the use of selective inhibitory... 

Figure 2.17 The structural analogs talopram 58 and citalopram 59 (upper compounds), as well as nisoxetine 60 and fluoxetine 61 (lower compounds), are chemically closely related. Whereas 58 and 60 (left compounds) are highly selective norepinephrine uptake inhibitors (selectivity factors of 550 and 180, respectively), the close analogs 59 and 61 (right compounds) are selective serotonin uptake inhibitors (selectivity factors of 3400 and 54, respectively).

M. Krieger, T. Kirchhausen, Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI. Proc. Natl. Acad. Sci. USA 2002, 99, 15422-15427. 

Daub, H., Godl, K., Brehmer, D., Klebl, B., Muller, G. (2004). Evaluation of kinase inhibitor selectivity by chemical proteomics. Assay Drug Dev. Technol. 2, 215-224. 

The observation of two distinct active site binding directions had critical impact on the design of novel class II type inhibitors in the course of the SmithKline Beecham medicinal chemistry effort. Our long term strategy for developing improved cathepsin K inhibitors had been to increase inhibitor selectivity by using electrophilic groups of lower intrinsic chemical reactivity than the aldehydes. It... 

Chemical inhibitors of proteases may be used to Inactivate the participating enz5nnes. lodoacetamlde and iodoacetate >prevent processing of virus proteins. Dlisopropyl fluorophosphate, probably acting as an inhibitor of a serine active-site protease, also prevents the processing of poliovirus polyprotein. Finally, chloromethyl ketones of selected amino acids, particularly that of phenylalanine, have been widely used in successful tests to block viral protein processing. The... 

Fig. 12.12 Chemical structures of some PPIase inhibitors selected by screening of libraries.

B. Klebl, G. Muller, Evaluation of kinase inhibitor selectivity by chemical proteomics, Assay Drug Dev. Technol. 

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