Potency concepts

Figure 4.5 Illustration ofthe concepts of potency that is, it is potent but not very effective. Inhibitor and effectiveness for two enzyme inhibitors. B shows less affinityfortheenzyme (high /<,), but Inhibitor A has a strong affinity for the enzyme it is a much more effective inhibitor when (low ff ), but even when it is maximally bound to maximally bound-that is, it is notvery potent but the enzyme it only achieves partial inhibition - is effective.

Some Chemical Considerations Relevant to the Mouse Bioassay. Net toxicity, determined by mouse bioassay, has served as a traditional measure of toxin quantity and, despite the development of HPLC and other detection methods for the saxi-toxins, continues to be used. In this assay, as in most others, the molar specific potencies of the various saxitoxins differ, thus, net toxicity of a toxin sample with an undefined mixture of the saxitoxins can provide only a rough approximation of the net molar concentration. Still, to the extent that limits can be placed on variation in toxin composition, the mouse assay can in principle provide useful data on trends in net toxin concentration. However, the somewhat protean chemistry of the saxitoxins makes it difficult to define conditions under which the composition of a mixture of toxins will remain constant thus, attaining a reproducible level of mouse bioassay toxicity is difficult. It is therefore useful to review briefly some of the chemical factors that should be considered when employing the mouse bioassay for the saxitoxins or when interpreting results. Similar concepts will apply to other assays. 

This leads to the concept of therapeutic index. The potency of a drug is almost irrelevant. It is its specificity that matters. Thus if two drugs A and B are effective at the same dose in a patient, say 1 mg, but A produces toxic effects at 10 mg which are only seen with 500 mg of B then B is clearly a much safer drug than A, in that patient. The ratio of toxic to effective dose is the therapeutic index (TI). It is often expressed as... 

The developments which led to the present day concepts of the metabolic activation of hydrocarbons did not arise from the classical approach of identifying metabolites of greater biological potency than the parent compound, but from an approach dependent upon the assumption (or presumption) that the interaction of carcinogens with DNA is a key event in the initiation of the carcinogenic process. Brookes and Lawley (49) found in 1964 that when radioactive hydrocarbons are applied to the skin of mice, they become covalently bound to the DNA of the skin. Moreover, the extents of binding to DNA for various hydrocarbons followed fairly closely their relative carcinogenic activities. 

Section 2 briefly outlines the identification of fragments where the optimisation is either not described, or only a limited amount of optimisation was achieved. Section 3 shows examples where lead molecules (<1 gM potency) were successfully derived from fragments. Finally, in Section 4 we give a commentary of key concepts, impacts and challenges for the field. 

Overall, several useful concepts emerge from these analyses. Different targets and routes of administration may require biased property distributions and screening libraries for successful lead optimization. This could influence the eventual chances of project success and should be taken into account early by project leaders. Once more, optimization focused on potency has been shown again to lead to larger molecules which increases the potential for poor ADME properties. The extent of any ADME issues would of course depend on the structure of lead molecule. Finally, larger, more lipophilic molecules historically have an increased rate of failure in the clinic. 

A number of recent publications indicate that the antibacterial field has adopted the concept of comparing free drug concentration at the site of action to in vitro drug potency reported as MIC [24-26]. A study of the antibacterial ertapenem in healthy volunteers was carried out to provide support for its use in skin and skin-structure infections [27]. Using microdialysis techniques, unbound drug concentrations in muscle and subcutaneous tissues were sampled at... 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

The general TTC concept, covering also carcinogenic effects, was introduced by Rulis (1986, 1989) as a Threshold of Regulation. Rulis used data on a subset of 343 oral carcinogens from animal smdies compiled in the Carcinogenic Potency Database (CPDB) (Gold et al. 1984). 

It is mentioned that the TTC concept has been incorporated in the risk assessment processes in a number of regulatory schemes as a scientifically sound tool to justify waiving or generation of animal data. It is also stressed that, in contrast to approaches such as read-across or chemical categorization, the use of the TTC is not focused or limited to the identification of potential hazards but also provides a quantitative estimate of potency. 

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