DERM 03: Chemistry of Topical Corticosteroids Flashcards
What contributes to a topical corticosteroid’s potency? (3)
- formulation and dose
- lipophilicity, solubility, and dissolution for drug penetration into skin (logP/TPSA ratio) – log P (hydrophobicity) correlates with potency, TPSA (number of heteroatoms) inversely correlates with potency
- optimal binding interactions between drug and glucocorticoid receptor (GR) – H-bonding (ie. 3-position on A ring), hydrophobic contacts (aka GR affinity – hydrophobic pocket, flattened 𝛼-ring)
What structural features increase adrenocorticoid (both GC and MC) activity?
- 9𝛼-F
- 9𝛼-Cl
- 17 𝛼-OH
- 21-OH, -SCH2F, -Cl
What structural features increase anti-inflammatory activity?
- 1-dehydro (prevalent)
- 6𝛼-F, 6𝛼-CH3
- 11𝛽-OH (prevalent)
- 16𝛼-, 17𝛼-esters (hydrophobic), acetonide
What structural features decrease mineralocorticoid activity?
- 6𝛼-CH3
- 16𝛼-, 16𝛽-CH3
- 16𝛼-OH
- 16𝛼-, 17𝛼-esteres (hydrophobic), acetonide
Low Potency Drugs
GR Interactions
GR:Hydrocortisone Complex
- 17⍺-OH pointing towards unoccupied hydrophobic pocket
- glutamine residue is flexible and capable of forming H-bond with 17⍺-OH in corticosteroids
Low Potency Drugs (2)
- hydrocortisone
- desonide
Low Potency Drugs
What are the structural features of hydrocortisone?
- Δ^4 3-keto
- 6𝛼-hydro
- 9𝛼-hydro
- 11𝛽-hydroxy
- 16𝛼-hydro
- 17𝛼-hydroxy
- C-21 hydroxy
Low Potency Drugs
What is a key feature of hydrocortisone acetate?
- acetate increases drug lipophilicity
- esterase removes acetate such that drug can bind GR
Low Potency Drugs
What is a key structural feature of hydrocortisone valerate?
achieves medium potency due to increased lipophilicity and hydrophobic interactions in GR hydrophobic pocket through valerate ester
(note: not a prodrug)
Low Potency Drugs
What are the key structural features of desonide? (2)
- Δ^1 double bond flattens A ring for improved GC activity (4x)
- 16𝛼-, 17𝛼-acetonide increases GC activity and decreases MC activity (in hydrophobic pocket)
Low and Medium/High Potency Drugs (1)
- fluocinolone
What are the unique structural features of fluocinolone acetonide and fluocinonide?
- Δ^1 double bond for increased GC
- 6𝛼-fluoro for increased GC activity
- 9𝛼-fluoro for increased activity and prevents 11-OH oxidation
- 16𝛼-,17𝛼-acetonide for increased GC activity, decreased MC activity, and improved receptor binding
- C-21 acetate improves skin penetrate
What are the unique structural features of fluocinolide?
- acetate increases drug lipophilicity
- esterase removes acetate
- can achieve medium to high potency due to higher dose and greater
lipophilicity, compared to its C-21 hydroxy analogue
Medium Potency Drugs
GR Interactions
GR:Mometasone Furoate Complex
- furoate ester anchors corticosteroid in (points toward) hydrophobic pocket
- flattened 𝛼-ring
Medium Potency Drugs (6)
- triamcinolone acetonide
- betamethasone
- C-21 modified – desoximetasone, clobetasone butyrate, mometasone furoate, fluticasone propionate
Medium Potency Drugs
What is the structure of triamcinolone acetonide?
similar to fluocinolone acetonide, but without 6𝛼-fluoro
Medium Potency Drugs
What are the structural features of betamethasone valerate?
- introduction of 16𝛽-methyl for decreased mineralocorticoid activity
- 17𝛼-valerate ester increases lipophilicity for better GR contacts, skin penetration, etc.
Medium Potency Drugs
What are the structural features of betamethasone dipropionate?
- C-21 and 17𝛼-propionate groups improve skin penetration
- prodrug form increases duration of action (slower onset)
- also categorized as high potency
Medium Potency Drugs
What can desoximetasone achieve and how?
can also achieve high potency due to formulation and higher dose
Medium Potency Drugs
What are the structural features of C-21 modified drugs?
- univalent isosteric replacement of hydroxyl group with chloro or SCH2F group on C-21 – increases lipophilicity, reduces TPSA, improves GR affinity
- note lipophilic variations to C-16 and C-17
- 9𝛼 substituent usually causes retention of urinary sodium F > Cl > Br (mineralocorticoid activity)
High Potency Drugs (3)
- amcinonide
- propylene glycol
- augmented betamethasone dipropionate
High Potency Drugs
What are the structural features of amcinonide?
- flattened 𝛼-ring increases activity
- fluorine atom stabilizes p-hydroxyl, increases activity
- esterification – prodrug
High Potency Drugs
What is augmented betamethasone dipropionate also categorized as and why?
also categorized as very high potency due to its formulation (propylene glycol)
Very High Potency Drugs (2)
- clobetasol propionate
- halobetasol proprionate
