medicinal or pharmaceutical chemistry of steroidal hormones for pharmacy student.

1. MEDICINAL
CHEMISTRY
OF STEROIDAL
HORMONES
Prepared by:
M.Abu ELfotouh ESSAM

2. M.Abu Elfotouh
Essential for anti-inflammatory activity
and for carbohydrate regulatory activity.
introduction of double bond between C1and
C2 improves glucocorticoid activity.
the presence of 3-keto-4-ene
Are essential for both
mineralocorticoids and glucocorticoids
activities.
Essential for anti-inflammatory activity
Cortisol Increases both GC and Mc activities.
R6=CH3 in prednisolone only improve glucocorticoids and decrease mineralocorticoids.
R6=F in Fluticazone increases only GC activity.
replacement of OH at C21 with halogen atom
improves lipophilicity and topical
anti-inflammatory activity.
Introduction of CH3 or OH groups enhance
the anti-inflammatory activity and eliminates
the mineralocorticoid activity.
introduction of F atom enhances both
glucocorticoids and mineralocorticoids
activities.

3. M.Abu Elfotouh
Natural glucocorticoids
hydrocortisone(cortisol) cortisone
structure essential for binding
with the receptor
site.
❖ Hydrocortisone is considered the standard glucocorticoid which has anti-inflammatory and salt
retention activities (1:1).
❖ It has topical anti-inflammatory activity.
❖ The 11ẞ-OH group is important for binding with the receptor site.
❖ The 11- keto function is reduced vivo to the 118-OH group.
❖ 21 Acetate hydrocortisone is superior to cortisone acetate as intra-articular injection
❖ Sodium succinate ester and sodium phosphate ester are water soluble and are used for I. v. for
emergency.
❖ Cortisone has 0.8.0.8 anti-inflammatory: salt retention ratio compared to the standard cortisol.
❖ It is an inactive metabolite of cortisol.
❖ It can also be considered as a prodrug of cortisol, because of the conversion to hydrocortisone in the liver
by 11ẞB-HSD type
❖ 2-Cortisone
❖ >Cortisone has no topical activity? due to the lack of the 118-OH group
❖ Cortisone has salt-retaining properties and is used as tablets or injection as replacement therapy in
adrenocortical insufficiency)
ester derivatives of hydrocortisone
Metabolism Of hydrocortisone
❖ Hydrocortisone is rapidly but reversibly metabolized to the inactive cortisone by 11B-hydroxysteroid
dehydrogenase type (11ẞ-HSD1).
❖ The11ẞ-HSD1 the liver " isozyme limits the oral use of hydrocortisone.
❖ Hydrocortisone is inactivated to cortisone by 11B-HSD type2enzyme in the kidney.
❖ This action helps in protecting the mineralocorticoid receptor which is a non-selective receptor from
being occupied by the glucocorticoids.
Deficiency of this enzyme results in Apparent
Mineralocorticoid Excess (AME syndrome)
hydrocortisone acetate

4. M.Abu Elfotouh
1. 9α -fluoro analogs of hydrocortisone
❖ 11times more potent than cortisone acetate but mineralocorticoid activity is increased 300-800 times.
❖ 9α-Fluoro substituent→↑ ionization of 11β- hydroxyl group by inductive effect (prevent metabolic oxidation of the 11B-OH group to ketone)
→ enhances interaction with the receptor through H bonding, thus increases both glucocorticoid and mineralocorticoid activities.
❖ Fludrocortisone acetate is used topically as an anti-inflammatory agent in ointments and lotions.
❖ Orally used as 21 acetate derivatives for mineralocorticoid replacement therapy in Addison's disease. (hypoadrenalism).
2-Δ1
-corticoids (1-Dehydro derivatives)
The search for glucocorticoid with improved anti-inflammatory and less mineralocorticoid activity
led to Δ1
-corticoids by introduction of double bond between C1 and C2 wich can be prepared
by microbial dehydrogenation of cortisone or hydrocortisone with Corynebacterium simplex.
Introduction of methyl group at C6 of prednisolone decreases mineralocorticoid activity.
Studies indicated that the A' corticoids may be used continuously,
in patients with rheumatoid arthritis without inducing gastrointestinal hazard.
2-Prednisone (Hostacortin) 2-Prednisolone (Hostacortin-H) Methyl Prednisolone (Depo-Medrol)
OR
HO
OH
CH3
R-H Methyl Prednisolone R-CH,CO-MethylPrednisolone acetate
- It has similar glucocorticoid activity as the parent compound prednisolone, but it has less sodium and potassium retention.
- The acetate ester is used for topical application while the water soluble sodium succinate ester is used for injection.
-The higher glucocorticoid activity and longer duration result from a combination of increased Hipophilicity and decreased metabolism due to the presence of
60-methyl group.
3. A corticoid +9 a-fluoro derivatives
1.Triamcinolone (Kenacort tab)
❖Prednisone and Prednisolone were obtained from cortisone and hydrocortisone,
respectively.
❖They are 3-4 times more potent as antiphlogistic agents as cortisone and hydrocortisone,
while their electrolytes activities were not proportionally increased.
❖Sodium phosphate and sodium succinate esters are water-soluble and is used by injection.
❖It has similar glucocorticoid activity as the parent compound prednisolone, but it has
less sodium and potassium retention.
❖The acetate ester is used for topical application while the water soluble sodium
succinate ester is used for injection.
❖The higher glucocorticoid activity and longer duration result from a combination of
increased lipophilicity and decreased metabolism due to? the presence of 6α-methyl
group.
R=H Fludrocortisone
R=CH3CO Fludrocortisone acetate
Anti-inflammatory Activity
(Glucocorticoid activity)
Salt retaining activity
(Miniralocorticoid activity)
R=H Methyl Prednisolone
R=CH3CO-MethylPrednisolone
acetate

5. M.Abu Elfotouh
3. - Δ1
corticoid + 9α -fluoro derivatives
1.Triamcinolone (Kenacort tab) 1.Triamcinoloneacetonide (Kenacort-A vial) 3.Dexamethasone 4-Betamethasone (Betaderm®)
This compound combines the structure
features of Δ1
corticoids and 9α-fluor
corticoids.
Introduction of 16 α-methyl hydroxyl
group into the molecule decreases the
mineralocorticoid activity and causes
(sodium excretion rather than sodium
retention
Intramuscular injection of triamcinolone is
effective and safe in the treatment of
dermatosis in combination with folic acid
antagonists (as methotrexate), it is
effective in the treatment of psoriasis.
➢A more potent derivative is triamcinolone
acetonide, a 16α-, 17 α -cyclic ketal
(isopropylidine derivative)
➢It is effective in the treatment of psoriasis and
other dermatological conditions.
➢This cyclic ketal derivative is prepared by
condensation with acetone.
➢More lipophilic& more active topically
➢8> fold triamcinolone (Topicort® Cr.).
➢Has a longer duration of action & greater side
effects systemically.
Useful for intra-lesional therapy (eg, intra-
articularly))
16α-methyl increases the anti-
inflammatory activity and reduces markedly
the salt-retaining properties of the
compound.
Dexamethasone has 7 times the anti-
inflammatory potency of prednisolone and
it is 30 times more potent than
hydrocortisone, with a longer duration of
action due to? presence of 16α- methyl
group.
It is used for circulatory collapse, trauma,
blood loss, myocardial infarction, and
different inflammatory conditions.
• Differs from dexamethasone in that [16
ẞ-methyl not al Slightly more active than
dexamethasone & has a longer duration
of action.
• Used in treatment of rheumatic
diseases and dermatological disorders.
Topical inhalation corticosteroids
1-Beclomethazone (Clenil) 2- Mometasone Furoate (Nasonex) 3-Fluticasone propionate (Flexonase*)
✓ It is the 9α-chloro derivative of betamethasone .
✓ Beclomethasone is potent glucocorticoid and the dipropionate
derivative is utilized in inhalation aerosol therapy for the treatment
of asthma and rhinitis.
Mometasone characterized by 21-chloro group which results in
compound 5-10 times more potent than betamethasone itself with
more rapid onset and greater affinity to GR than most glucocorticoids.
Used as topical corticosteroid and also as intranasal metered dose spray
for treatment of allergy (used as furoate ester)
The combination of 21-C1 and the furoic acid ester C17 provides the
highest glucocorticoid receptor affinity of any topical corticosteroid.
• It has unique C20 thiofluormethyl group that in
combination with 17α propionate ester gives it 36-fold
gluco-corticoid receptor affinity as compared to
Beclomethasone dipropionate.
• 9α-F, increases both gluco- and mineralocorticoid activity
and 6 α-F enhances only glucocorticoid activity.
• Both are used as inhalation in the treatment of allergic
rhinitis and asthma.
CH3
CH3
9α-Fluoro-16β-methylprednisolone
9α-Fluoro-16 α -methylprednisolone
Beclomethazone R = H
Beclomethazone dipropionate R= C₂H5CO

6. M.Abu Elfotouh
mineralocorticoids
Mineralocorticoid antagonists
Spironolactone (Aldactone)
▪ Spironolactone (potassium sparing diuretic) is an aldosterone antagonist, as it binds to the mineralocorticoid
receptors in the kidney and results in diuretic response (increased Na excretion and W retention).
▪ The 3-keto-4-ene at A-ring is essential for recognition by the receptor.
▪ The 7α-substituent is essential for the antagonistic activity.
Glucocorticoid and Mineralocorticoid Biosynthesis Inhibitors
Trilostane
▪ This compound inhibits (blocks) hydroxylating enzymes (hydroxylases) involved in hydrocortisone
and aldosterone biosynthesis.
▪ It is used for the treatment of Cushing's disease (excessive formation of adrenocorticoids).
Due to absence
of 11β-OH
Trilostane