1. the type of group introduced;
2. whether the introduction is reversible or irreversible;
3. the position of incorporation and
4. the chemical route of introduction.
3.6.1 The type of group
The incorporation of polar groups, such as the alcohol, amine, amide, carbox-
ylic acid, sulphonic acid and phosphorus oxyacid groups, which either ionize
or are capable of relatively strong intermolecular forces of attraction with water
(hydrogen bonding), will usually result in analogues with an increased
water solubility. Acidic and basic groups are particularly useful, since these
groups can be used to form salts (see section 3.5), which would give a wider
range of dosage forms for the final product. However, the formation of zwitter-
ions by the introduction of either an acid group into a structure containing a
base or a base group into a structure containing an acid group can reduce water
solubility. Introduction of weakly polar groups, such as carboxylic acid esters,
aryl halides and alkyl halides, will not significantly improve water solubility and
can result in enhanced lipid solubility. In all cases, the degree of solubility
obtained by the incorporation cannot be accurately predicted since it also
depends on other factors. Consequently, the type of group introduced is gener-
ally selected on the basis of previous experience.
The incorporation of acidic residues into a lead structure is less likely to
change the type of activity, but it can result in the analogue exhibiting haemo-
lytic properties. Furthermore, the introduction of an aromatic acid group
usually results in anti-inflammatory activity, whilst carboxylic acids with an
alpha functional group may act as chelating agents. Basic water solubilizing
groups have a tendency to change the mode of action, since bases often interfere
with neurotransmitters and biological processes involving amines. However,
their incorporation does mean that the analogue can be formulated as a wide
variety of acid salts. Nonionizable groups do not have the disadvantages of
acidic and basic groups.
3.6.2 Reversibly and irreversibly attached groups
The type of group selected also depends on the degree of permanency
required. Groups that are bound directly to the carbon skeleton of the lead
66 AN INTRODUCTION TO DRUG DISCOVERY