Medicinal Chemistry

(Jacob Rumans) #1

the form of its acetomide (an acetone ketal), shows a 9α-fluoro group in addition to ∆^1
unsaturation, and a 16α-OH. It is used in treating psoriasis and other dermatological
problems. Dexamethasone (5.65), perhaps the most active and highly stable glucocor-
ticoid, is the 16α-methyl analog of triamcinolone. It is interesting to note that proges-
terone binds well to the glucocorticoid receptor despite a missing 11-oxygen functional
group, but it fails to elicit gene activation in glucocorticoid target cells, thus shedding
light on the role of the 11-OH group.
The optimum glucocorticoid structure shows a 1α,2β-half-chair conformation for
ring A, with ring D as a 13-envelope (C-13 is bent up) or a half-chair. Halogenation is
most effective in positions 6, 7, 9, and 12. The compounds bind on their βface by
hydrophobic binding forces.


5.12.3 Glucocorticoids: Pharmacological Activity

The most important clinical application of glucocorticoids and their semisynthetic
analogs is their anti-inflammatoryactivity, discovered in 1949 by Hench and co-workers.
The profound anti-inflammatory effects of glucocorticoids arise from the combined
effects of these steroids on both the cellular and molecular mediators of inflammation;
these effects are separate from the metabolic effects described above and further indi-
cation of the widespread diversity of macromolecules to which steroids can bind.
Glucocorticoids suppress inflammation at the cellular level by downregulating the con-
centration, distribution, and function of leukocytes(white blood cells) that profoundly
influence inflammation and response to infection within the body (In this way, steroids
help to mediate the overlap between the endocrine systems [chapter 5] and the immune
systems [chapter 6]). Glucocorticoids also suppress inflammation at the molecule level
by suppressing inflammatory cytokines, chemokines, and other molecular mediators of
inflammation.
From a clinical perspective, the anti-inflammatory effects of glucocorticoids are
extremely important and in some cases life saving. While initially revolutionizing the
symptomatic treatment of osteoarthritis and rheumatoid arthritis, these drugs did not
provide a lasting cure for these crippling, painful, and widespread diseases. Moreover,
any benefits in disorders such as arthritis were more than negated by the potential for
severe long-term side effects that are inevitable with prolonged use of steroids.
Despitethese limitations, anti-inflammatory glucocorticoids have found clinical use in
many other systemic inflammatory diseases (e.g., systemic lupus erythmatosus). Anti-
inflammatory glucocorticoids have also been used to suppress pathological inflam-
mation in various organ systems, including the heart (myocarditis, pericarditis), lungs
(pneumonitis, allergic bronchitis, asthma), bowel (regional ileitis, Crohn’s disease), and
skin (dermatitis). In the case of skin symptoms, the external application of steroid drugs
is possible, eliminating many systemic side effects. Patients suffering from acute
leukemia and lymphoma (especially Hodgkin’s disease) may also benefit from gluco-
corticoids. Anti-inflammatory steroids have been used to treat exacerbations of multi-
ple sclerosis and to prevent strokes and blindness in patients with temporal arteritis
(inflammation of the temporal artery blood vessel).
Glucocorticoids are also used as hormonal replacement therapy in patients in whom
the adrenal cortex has been destroyed by some pathological process. The resulting


HORMONES AND THEIR RECEPTORS 335
Free download pdf