compound by less reactive C–C, C–O and C–N bonds are likely to be irrevers-
ibly attached to the lead structure. Groups that are linked to the lead by ester,
amide, phosphate, sulphate and glycosidic links are more likely to be metabol-
ized from the resulting analogue to reform the parent lead compound as the
analogue is transferred from its point of administration to its site of action.
Compounds with this type of solubilizing group are acting as prodrugs
(see section 9.8) and so their activity is more likely to be the same as the
parent lead compound. However, the rate of loss of the solubilizing group will
depend on the nature of the transfer route, and this could affect the activity of
the drug.
3.6.3 The position of the water solubilizing group
In order to preserve the type of activity exhibited by the lead compound, the
water solubilizing group should be attached to a part of the structure that is not
involved in the drug–receptor interaction. Consequently, the route used to
introduce a new water solubilizing group and its position in the lead structure
will depend on the relative reactivities of the pharmacophore and the rest of the
molecule. The reagents used to introduce the new water solubilizing group
should be chosen on the basis that they do not react with, or in close proximity
to, the pharmacophore. This will reduce the possibility of the new group
affecting the relevant drug–receptor interactions.
3.6.4 Methods of introduction
Water solubilizing groups are best introduced at the begining of a drug
synthesis, although they may be introduced at any stage. Introduction at the
begining avoids the problem of a later introduction changing the type and/or
nature of the drug–receptor interaction. A wide variety of routes may be used to
introduce a water solubilizing group; the one selected will depend on the type
of group being introduced and the chemical nature of the target structure
(Figures 3.6 and 3.7). Many of these routes require the use of protecting agents
to prevent unwanted reactions of either the water solubilizing group or the lead
structure.
THE INCORPORATION OF WATER SOLUBILIZING GROUPS IN A STRUCTURE 67