• Carbohydrate biosynthesis (activates glycogen synthesis)
• Lipid biosynthesis
• Protein Biosynthesis:inhibits activity
• Immune function: supresses it
• Cellgrowth/death: supresses growth, promotes apoptosis

Therapeutic goal of Adrenocorticosteroids

1. C3 has a keto side chain
2. C4,5 are double bonded
3. C11 has a beta (inactive)keto or (active)hydroxy group
4. C 17 has a beta ketol side chain
5. C21 has a terminal OH
6. C17 has a alpha hydroxy group

1. C 21: Modifications create prodrugs. Hydrophilic groups have rapid activity, hydrophobic groups are long lasting. C21 Chlorine potentiates activity.
2. C 9alpha: Adding an ectron withdrawing group increase glucocorticoid activity x10 and mineralocorticoid activity x300-800x. If C16 group is added it blocks mineralocorticoid activity.
3. C 1,2: Double bond increases glucocorticoid activity.
4. C 6alpha side chain blocks catabolism.
5. C 16 side chain. Supresses mineralocorticoid activity. Also can block C 17 catabolism.

Methylprednisolone

C6 alpha side chain. Causes blocking of catabolism

Triamcinolone(Adrenocorticosteroid)

C16 addition leads to low mineralocorticoid activity.

C9 modification increases receptor activity. 

Triamcinolone acetonide(Adrenocorticosteroid)

• C 16 side chain is lipophilic. Lead to low mineralocorticoid activity.
• C 9 modification increases Receptor activity.

Dexamethasone(Adrenocorticosteroid)

• Catabolically blocked: prevents C 17 attack
• Greater activity per dose amount than prednisolone, but about equal usefulness in therapy

Betamethasone(Adrenocorticosteroid):

• Catabolically blocked: prevents C 17 attack
• Greater activity per dose amount than prednisolone, but about equal usefulness in therapy

Paramethasone (Adrenocorticosteroid):

• Catabolically blocked: prevents C 17 attack
• Greater activity per dose amount than prednisolone, but about equal usefulness in therapy

Fluandrenolone (Adrenocorticosteroid):

Topical

Flucinolone (Adrenocorticosteroid):

Topical

Fluorometholone (Adrenocorticosteroid):

Topical

Fluprednisolone (Adrenocorticosteroid):

Topical

Halcinonide (Adrenocorticosteroids):

1. Highly active topical ACS
2. C21 Chlorine potentiates activity

Clobetasol/Halobetasol proprionate (Adrenocorticosteroid)

• Highly Active topical Adrenocorticosteroids
• C21 Chlorine potentiates activity

Fluticasone proprionate/FlonaseR (Inhaled ACS):

• C16aCh3 increase lipophilicity.
• High receptor activity.
• Very high systemic metabolism
• C16 blocks catabolism

Beclomethasone diproprionate (Inhaled ACS):

• Prodrug
• Lipophilic
• C16 blocks catabolism

Mometasone Furoate/Nasonex (Inhaled ACS):

• Lipophilic
• C16 blocks catabolism and increases lipophilicity.

Estrone (Estrogen):

E2> estrone > Estratriol

17-Beta Estradiol

E2> Estrone> Estriol

Estriol (Estrogen):

An antagonist

• Therapeutic goal 1: Develop a very easily administered form for contraception. i.e. an orally active form.
• Develop a form that is atheroprotective & and cognition and bone preserving without causing Cancer.
• Blocking catabolism will prolong lifetime and make estrogens orally active.

Estrogens

• C3 has a -OH side chain
• C17 has a beta -OH side chain
• A ring is fouly double bonded
• Does not require a steroid nucleus. It is critical that the OH groups are seperated by the right distance.

Ethinyl Estradiol (Synthetic Estrogens)

• Blocks catabolism of C17alpha ethinyl

Estradiol Valerate/Natazia(Estradiolvalerate and dienogest)

• Increase active lifetime by creating prodrugs with either C3 or C17 or both (Hydroxyls are derivatized)

Dienogest (Synthetic estrogens)

Increase active lifetime by creating prodrugs with either C3 or C17 or both (Hydroxyls are derivatized)

Stilbene (Estrogenic Compounds lacking a steroid nucleus)

• High activity without an intact nucleus
• Highly active

Diensetrol (Estrogenic Compound lacking the steroid nucleus)

• High activity without an intact nucleus
• Highly active

Hexestrol (Estrogenic Compound lacking the steroid nucleus)

• High activity without an intact nucleus
• Highly active

Benzestrol (Estrogenic Compound lacking the steroid Nucleus)

• High activity without an intact nucleus
• Highly active

Chlorotrianese (Estrogenic compounds lacking steroid nucleus)

• Long lived in body slowly released

Genistein (Xenoestrogens)

Isofavenoid with weak estrogen activity

• Impeded Estrogens: Compete for binding, bind weakly and do not activate (Estriol)
• Triphenylethylenes: Bind strongly but do not activate
• Aromatase inhibitors: Block conversion of androgen precursors into estrogens.

Aromasin/ Exemestane

Antiestrogens: Aromatase inhibitors

Prodrug

Irreversible suicide inhibitor

Metabolized by cyp 3A4

• The main therapeutic use is for contraception
• Develop a very easily administered form for contraception i.e. orally-active form
• Steroid nucleus structures in the estrane, androstane, and pregnane class all can activate the progesterone receptor

1. C 17 alpha blockade avoids catabolism.
2. C 6 side groups help blocking catabolism.
3. Removal of the C 19 methyl increases activity.
4. C17 Beta configuration is required for activity.

Progesterones

1. Requires an intact nucleus and the 4-5 double bond
2. Not required: C20-21 promote binding.
3. Forms lacking C3 keto can still be active prodrugs.
4. Does not require a C19 side chain.

17 alpha blocked progesterones (Progesterones)

• OR blocks catabolism of the required C17beta side chain. Acetate has a weak oral activity. The caproate has a stronger oral activity.

Medroxyprogesterone Acetate (Catabolically blocked Progesterones)

1. Blocked in C 17 and in C 6 position

Megestrol acetate ( Catabolically blocked progesterones)

• Blocked at C 17 position and at the C 6 position.

Chlormatidone acetate (Catabolically blocked Progesterones)

• Blocked at C 6 and C 17 position

Demethyl Progestins

• Removal of C 19 methyl increases activity. 
• C 17 beta configuration required for activity.

Demethyl progestins

• Removal of C 19 methyl increases activity.
• C 17 beta configuration required

4th Generation demethyl progestins

• High activity at the progesterone receptor (C 19 removal)
• Low activity at other steroid Receptor

Androstane Based Progestins

• Two Carbons in the C 17 alpha side chain block catabolism. And provide activation of progesterone receptor.
• Dimethisterone contains a second catablolic blocking group at the C6.

Androstane demethyl progestins

• C 17 double C activate progesterone receptors and catabolically block the compound. 
• C 19 demethyl increases activity

Demethyl Androstane Progestins

• Gonanes
• Adding an additional C 18 increases receptor binding.
• Desogestril and Norgestimate have decreased androgenic side effects

• C3 keto is not required
• C 17 has a beta OH side chain
• 4,5 double bond is inhibitory.
• Many modifications are tolerated
• Can remove C 19 methyl group to make nor form with higher anabolic activity

• C 17 catabolic blockade creates orally active form
• C 17 acetoxy makes it a prodrug.
• Increased activity when C19 is removed.
• C 2 keto is dispensible.