Drug Metabolism in Drug Design and Development Basic Concepts and Practice

results (Fig. 8.1). Systematic decision trees can be employed to allow clear
pathways for evaluation of new compounds. Alternatively, screens can be run
in parallel so that all information is generated for all compounds. This strategy
makes workflows simpler and increases efficiency but can lead to information
overload and complex decision making.
For metabolic stability screens to be most effective, the screens must be
tightly linked to some means of gathering information on metabolite structure.
Methods for rapidly determining metabolite molecular weight and limited
structural information have improved dramatically and allow this approach to
be routinely employed (Anari and Baillie, 2005; Watt et al., 2003). The goal of
this type of approach is to allow the identification of metabolic ‘‘soft spots’’
which can then be altered to produce compounds with improved metabolic
stability. The literature of successful structural modification to increase
stability has recently been reviewed (Thompson, 2001).

8.2.5 In silicoMethods to Study Metabolism

Metabolism prediction throughin silicomethods may be possible in the future,
although there is still a great deal of technical development needed before it is a
viable alternative (van de Waterbeemd and Gifford, 2003). Predictive
metabolism programs may allow metabolism scientists and medicinal chemists
to obtain metabolic rate or site of metabolism information prior to first
synthesis of compounds. The majority of the methods in this area that have

Lead compound

Advanced lead compound

Optimized candidate

Addition/

deletion

of screens

Characterization of ADME properties

Design of in vitro screens to address candidate “developability”

Characterization of ADME properties––

validation of in vitro model

Further screening

FIGURE 8.1 Scheme for incorporation of ADME-based developability screen during
the candidate optimization phase of the drug discovery process.

244 DRUG METABOLISM RESEARCH