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What type of substitution at C9 and C6 will enhance gluco and mineralo corticoid activity?
Alpha Halogens (like F)
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Substitution at this point has what effect on the molecule?
Tends to decrease mineralo activity
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What are the significant characteristics of this group?
- Site of metabolism
- Protection can be achieved by creating an ester
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What groups are accommodated at this point?
OH or F are required for Mineralo and Gluco acitivty
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This group is significant for what reasons?
- Required for gluco activity
- Can be metabolized reversibly to a weakly active ketone
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What is the significance of this group?
- Methyl protects against inactivating metabolism
- Provides steric hindrance to A ring reduction to a 5B-H, 3a-OH metabolite
- 70% reduction in this reaction
- Enhanced receptor affinity leading to 10x increase in GC activity and string MC activity
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What is the significance of the 3-keto and delta 4,5?
Essential for Gluco and Mineralo activity
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What is the significance of this additional double bond between 1 and 2?
- Extends the resonance
- Stabilizes the A ring
- Electronically inhibits A ring reduction
- Additional sp2 carbons flatten the A ring for 3-5x GC activity enhancement
- Reduces MC activity by 0.6-0.8x
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A Delta 1, 4, 6 compound, has what characteristics beyond a delta 1, 4 compound?
- Extended resonance into the B ring
- Increases GC activity
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A halogen at this location (9a) would have what effect on the molecule and through what mechanism?
- Enhanced GC activity by e- withdraw on the 11B-OH, increasing the –OH’s affinity for H bonding to the receptor
- Electronic pull decreased Oxidation of 11B-OH by 67%
- F at this position would enhance MC activity
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When would you see an F at this position and when would you see a Cl?
- Cl would be for topical only due to enhanced lipophilicty over F
- F would be used for enhanced GC or MC activity
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How can you enhance Mineralocorticoid activity?
- Add a 9a-F or a 12a-F
- Increased 300-800 fold with these adjustments and no MC abolishing groups
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Would a 9 beta or 12 beta Flourine enhance mineralcorticoid activity?
No, need to be alpha, because MC receptor interactions are with the alpha face
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Functional groups at what positions are used to abolish MC activity at therapeutic doses?
- C6 and C16
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What effect does a 16a-OH have on this molecule?
- Abolishes MC activity
- Decreases glucocorticoid affinity
- Slows oxidation to the inactive 17-keto steroid by 70%
- The two effects above = Glucocorticoid activity increases due to a 2-fold increase in DOA
- Lipophilic pocket on GC receptor repels this group
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What effect does a 16a or 16B-CH3 have on this molecule?
- Abolishes MC activity
- Lipophilic pocket on the GC receptor accepts the C16-CH3 (a or B form) to form a hydrophobic bond
- Increases GC activity 12x over no C16 substiuent
- Slows C17 inactivation
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How does the GC activity compare between a steroid with a 16a-OH and one with a 16-CH3?
16-CH3 in either a or B form, promotes a 6-fold increase in glucocorticoid activity over the 16a-OH
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What effects does a 6a-CH3 group impart?
- Abolishes MC activity
- Provides a slight increase in GC activity resultant of an increase in DOA due to steric inhibition of A ring reduction
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What effects does a 6B-CH3 group impart?
- Does not abolish MC activity, slight increase in MC activity
- Slight Increase in GC activity due to DOA, as a result of steric inhibition of A ring reduction
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What effects does a 6a-F group impart?
2-fold increase in glucocorticoid potency over the 6a-CH3
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Order the possible groups at C6 from most to least GC activity enhancing:
F > Beta CH3 > alpha CH3
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Order the possible groups at C6 from most to least MC activity abolishing:
alpha CH3 > Beta CH3 or F
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In what way can you use a topical steroid to treat psoriasis (a disease normally resistant to steroids)?
Use an occlusive dressing
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Topical corticoids are all highly hyro or lipo –philic?
Lipophilic
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What type of structures are particularly common in topical steroids?
Lipophilic esters, diesters, acetonides, and halogenated molecules (C21)
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Can systemic steroids have a C21 halogen?
No, strictly OH (or ester that is hydrolyzed to and OH)
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Mometasone has a furan ring part of the ester at the –C17 α-OH, what effect does this have?
Enable it to penetrate into the skin and stay there (not penetrate to the systemic circulation)
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Amcinonide has a cyclopentane forming the diether of the Hexacetonide, what effect does this have?
Enable it to penetrate into the skin and stay there (not penetrate to the systemic circulation)
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Alcometasone has a unique C7 α-Cl, what effect does this have?
Enable it to penetrate into the skin and stay there (not penetrate to the systemic circulation)
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Fluticasone has a unique C20 fluoro methyl thio ester group, what effect does this have?
Enable it to penetrate into the skin and stay there (not penetrate to the systemic circulation)
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Will topical corticoids be used for GC or MC activity?
GC only
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Functional groups with what type of activity will usually be found on topical corticoids?
- GC enhancing groups
- MC diminishing groups at 6 or 16
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Fluid retention can occur if only a small amount of topical corticosteroid penetrates the skin and reaches the blood stream, groups with what action can diminish this effect?
MC diminishing groups (at 6 and 16)
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