4.2 Changing size and shape
The shapes and sizes of molecules can be modified in a variety of ways, such as
changing the number of methylene groups in chains and rings, increasing or
decreasing the degree of unsaturation and introducing or removing a ring
system (Table 4.1). These types of structural change usually result in analogues
that exhibit either a different potency or a different type of activity to the lead.
4.3 Introduction of new substituents
The new substituents may either occupy a previously unsubstituted position in
the lead compound (see section 4.3.1) or replace an existing substituent (see
section 4.3.2). Each new substituent will impart its own characteristic chemical,
pharmacokinetic and pharmacodynamic properties to the analogue. Over the
years, a great deal of information has been collected about the changes caused to
these properties of a lead compound when a new substituent is incorporated into
its structure. As a result, it is possible to generalize about some of the changes
caused by the introduction of a particular group into a structure (see Table 4.2).
However, the choice of substituent will ultimately depend on the properties that
the development team decide to enhance in an attempt to meet their objectives.
Moreover, it should be realized that the practical results of such a structural
change will often be different from the theoretical predictions.
4. 3. 1 The introduction of a group in an unsubstituted position
The incorporationof anygroupwillalwaysresultin analogueswitha different size
and shape to the lead compound. In addition, it may introduce a chiral centre,
which will result in the formation of stereoisomers, which may or may not have
different pharmacological activities (Table 2.1). Alternatively, it may impose
conformation restrictions on some of the bonds in the analogue (Figure 4.2).
The introduction of a new group may result in an increased rate of metabol-
ism, a reduction in the rate of metabolism or an alternative route for metabolism
(see Chapter 9). These changes could also change the duration of action and the
nature of any side effects. For example, mono- and diortho-methylation with
respect to the phenolic hydroxy group of paracetamol produces analogues with
CHANGING SIZE AND SHAPE 73