MD-4

LOs:

Essential functionality for steroid anti-inflammatory activity (oxygen at C-11)

Key structural modifications to increase glucocorticoid selectivity and potency – flatten A-ring, C-9 electron withdrawing substituent, esters-C17 / cyclic acetals C16,17.

C16-methyl (selectivity only)

Modifications at the 6-position do not affect potency and are commercial (patent avoidance)

Understand the concept of a prodrug and be able to apply first-year Med. Chem. to show the mechanism for hydrolysis of beclometsone diesters to beclometasone (do not need to learn structures but apply knowledge).

Explain why hydrocortisone 17-butyrate is much more potent than hydrocortisone.

Explain why clobetasol is much more potent than clobetasone as a topical steroid.

Know the different potencies of the topical steroids mentioned in the lecture – hydrocortisone (mild up to 2.5% w/w), clobetasone butyrate (moderate at 0.05% w/w), hydrocortisone butyrate (potent at 0.1% w/w), clobetasol propionate (very potent at 0.05% w/w).

Know that the potency of the steroid should match the severity of the condition in eczema. Mild eczema – use mild steroids, moderate eczema – use moderately potent steroids etc.

Know why there is a significant different in dose when steroids are administered via the oral route, compared with topical / inhalation

For above, consider: first pass metabolism, distribution, concentration at site of action

Absorption of topical corticosteroids is improved by increasing the lipophilicity (within reason, in general – LogP <5)

Converting hydroxyl FG/alcohols into esters is generally an easy win for increasing lipophilicity