experimental conditions. It is also common for them to be tested in fully functional
assays and at the same time checks will be made on their potential patentability. The
molecular structure of the confirmed hits will then be compared to identify common
structural features that can then be built into a newly synthesised series of candidate
drugs. The technique ofcombinatorial chemistry is widely used by medicinal
chemists to synthesise a large number of structurally related compounds on a small
scale. These compounds are then screened for activity to identify further important
structural features and the process repeated on an iterative basis. At the same time,
attention will be paid to the physical properties of the emerging ‘lead’ compounds. For
a compound to be an effective therapeutic agent it needs to possess a number of
important physical and biological properties. These include a balanced water/lipid
solubility expressed by its logPvalue, the extent to which it binds to human albumin,
its interaction with the human cytochrome P450 system and its lack of toxicity.
Simplein vitroscreening methods are available for these properties without resorting
to animal studies. The potential selectivity of the compounds will also be evaluated
against other related physiological targets. The application of these various tests
enables compounds with inappropriate properties to be rejected at an early stage.
Pharmacological and toxicological profiling
The purpose of these studies is to evaluate the full pharmacodynamic profile of
the compounds in order to establish that they possess the required molecular and
cellular properties in tissues and animals, that they possess adequate potency, efficacy
and selectivity, appropriate pharmacokinetic properties and that repeated dosing with
the compound or its withdrawal after repeated dosing do not lead to toxic effects.
Such profiling will be undertaken using bothin vitroandin vivomethods. Studies
are likely to include evaluation in animal cell lines expressing cloned human genes
and animal models to study both acute and chronic physiological, pharmacological
and toxicological properties. The outcome of the drug discovery phase is the identifi-
cation of a drug candidate, with a few ‘back-up’ candidates, for development as a
licensed drug.
18.3 Drug development
At the end of the drug discovery process the management team will know that the
candidate drug has displayed encouraging properties in the screening programme and
has appropriate physical and pharmacokinetic properties for clinical use. The team
will also have reason to believe that the intellectual property represented by the
drug can be protected by international patents. At this stage, however, the group
has no evidence that it will display acceptable efficacy, potency and selectivity
in human subjects. Thus the priority is to obtain ‘proof of concept’ that the drug
will demonstrate the anticipated clinical properties. To achieve this, data from
human subjects are needed and this is the initial priority of the development phase.
Unlike the discovery process, the development phase is highly prescribed in that it
727 18.3 Drug development
