Medicinal Chemistry of Corticosteriods

corticosteroids and sex hormones

What are the 2 classes of steroids?

corticosteroids

are classified as mineralocorticoids and glucocorticoids

endogenous

Aldosterone, cortisol, and cortisone are ___________ corticosteroids

sex hormones

are classified as estrogen, progesterone, and testosterone

Corticosteroids

• Anti-inflammatory agents and immunosuppressants

• Also called glucocorticoids

• Control metabolism of carbohydrates, protein, and lipids

• Some display mineralocorticoid activity (~salt retention)

• Cortisone and cortisol are endogenous glucocorticoids

• Three major groups: systemic, topical, and inhaled

Hydrocortisone

-Glucocorticoid activity: Anti-inflammatory agents

-Limited use of mineralocorticoids (Na+/K+ balance)

• Anti-inflammatory glucocorticoid

• Active in topical applications

• Half-life is 1.5 hours (~similar to cortisone)

Cortisone

-Hydrocortisone interconverted to __________

-has 80% activity of hydrocortisone

• Weak anti-inflammatory glucocorticoid

• Minimal activity from topical application

• 80% activity of hydrocortisone

• C11 reduction converts to hydrocortisone

5 beta-reductase and 6 beta-hydroxylase

How are Hydrocortisone and Cortisone inactivated?

cortisone acetate

• C21 ester prodrug of cortisone

• Anti-inflammatory agent

• Moderate salt retention

Fludrocortisone acetate

• C9 fluorinated analogue of cortisone acetate

• 10X anti-inflammatory than hydrocortisone

• 250X salt-retention than hydrocortisone

Prednisone (Deltasone®)

• C1,2 alkene analogue of cortisone

• 4X inflammatory activity than hydrocortisone

• 1/3 salt retention than hydrocortisone

• Reduced metabolism (half-life is 2 hours)

Prednisolone (Millipred®)

• C1,2 alkene analogue of hydrocortisone

• 1.25X inflammatory activity than prednisone

• Reduced metabolism (half-life is 3 hours)

Methylprednisolone (Methapred®)

• C6 methyl analogue of prednisolone

• Similar potency to prednisolone

• Reduced metabolism (half-life is 3.5 hours)

Dexamethasone (DexPak®)

• C9 fluorine, C16 methyl analogue of prednisolone

• C16 methyl reduces metabolism (half-life is 4 hours)

• 6X anti-inflammatory activity of prednisolone

• No mineralocorticoid activity

Betamethasone (Celestone®)

• Similar to dexamethasone

• C16 methyl group epimer (stereocenter flip)

Deflazacort (Emflaza®)

• C16/C17 dihydroxazole analogue of prednisolone

• C21 ester prodrug

• No mineralocorticoid activity

Triamcinolone acetonide (Kenalog®)

• C16/C17 acetonide analogue of dexamethasone

• Similar potency to prednisolone

• No mineralocorticoid activity (from acetonide)

Topical Corticosteroids

• Unusually highly potent agents

• Display many halogens to enhance potency and/or block

metabolism

• Same structure-activity relationships as systemic corticosteroids

• Hydrocortisone, betamethasone, and triamcinolone are also

topical agents

Fluocinolone acetonide (Capex®)

• C6 fluorine analogue of triamcinolone acetonide

• 2-3X more potent than triamcinolone acetonide

• Review of structure-activity relationships:

• C1,2 alkene increases anti-inflammatory

• C9 fluorine increases anti-inflammatory

• C16/C17 acetonide has no mineralocorticoid activity

• C6 fluorine increases anti-inflammatory activity

Clobetasol (Clobex®)

• C21 chlorine, C17 ester analogue of betamethasone

• C21 chlorine replaces alcohol and increases potency

• Highly potent, 120X activity of triamcinolone

• Not a prodrug

Halobetasol (Ultravate®)

• C6 fluorine analogue of clobetasol

• C6 fluorine increases potency

• Highly potent, 120-140X activity of triamcinolone

Mometasone furoate (Nasonex®)

• C9 chlorine, C17 furoate analogue of clobetasol

• C9 chlorine is 1/3 relative potency of fluorine

• 40X potency of triamcinolone

Halcinonide (Halog®)

• C21 chlorine, C1,2 saturated analogue of triamcinolone acetonide

• C1,2 single bond reduces potency

• 10-15X potency of triamcinolone

Desoximetasone (Topicort®)

• C17 deoxy analogue of dexamethasone

• Lacks C17 alcohol, reduces potency

• Half potency of dexamethasone

Desonide (Desonate®)

• C9 non-fluorinated analogue of triamcinolone acetonide

• Lacks C9 fluorine, reduces potency

• Half potency of triamcinolone acetonide

Clocortolone (Cloderm®)

• C6 fluorine, C9 chlorine, C17 deoxy, C21 ester analogue of dexamethasone

• Inactive prodrug

• Similar potency to triamcinolone acetonide

• Review of structure-activity relationships

• C6 fluorine increases potency

• C9 chlorine reduces potency

• C17 deoxy reduces potency

Aclomethasone (Actovate®)

• C7 chlorine, C9 non-fluorinated analogue of dexamethasone

• C7 chlorine moderately increases potency

Difluorasone (Psorcon®)

• C6 fluorine analogue of betamethasone

• 2-3X more potent than betamethasone