(and anti-inflammatory) actions but lacking in mineralocorticoid effects and side
effects. Substituents added to the cortisol molecule may alter bioactivity and receptor
binding affinity independently of other functional groups present on the molecule.
While a high receptor binding ability does not necessarily reflect overall pharmacolog-
ical activity, it is an important factor in glucocorticoid drug design. Two of these impor-
tant modifications are as follows:
- Halogenation. 9 α-Fluorocortisone is only about 10 times more active than its parent
compound, but its mineralocorticoid activity is 300–600 times greater. This is unde-
sirable since it leads to edema; thus, the compound fludrocortisone (5.62) is used
only topically, in ointments. - Additional double bonds.∆^1 -compounds (where ∆^1 indicates the position of a double
bond) were introduced, like prednisone (3.7), a ∆^1 -1l-ketone, and prednisolone, its
11-hydroxy analogue. Changing the geometry of the A ring increased the potency
without augmenting mineralocorticoid activity.
The introduction of a methyl group in methylprednisolone (5.63) resulted in a slight
increase in activity; however, the greatest improvements in activity came from the com-
bination of a double bond, halogen, and methyl substituents. Triamcinolone (5.64), in
334 MEDICINAL CHEMISTRY