Fluoro mineralocorticoids

The introduction of a 9a-fluoro substituent increases anti-inflammatory activity, but it increases mineralocor-ticoid activity even more (300x). Fludrocortisone acetate is of little value as an anti-inflammatory, but it is employed as a mineralocorticoid. On the other hand, additional modifications may be employed. Introduction of a 1,2-double bond increases glucocorticoid activity over mineralocorticoid activity, and a 16-methyl group reduces mineralocorticoid activity without affecting glucocorticoid activity. A combination of these three structural modifications gives valuable anti-inflammatory drugs, e.g. betamethasone, with hardly any mineralocorticoid activity. ... 

On the hypothesis that the side chain could perhaps be stabilized against such metabolic inactivation by an appropriately placed but otherwise chemically inert substituent, some analogues of cortisone containing a 16a-methyl group were synthesized by Arth et al. [20] in the expectation that the 16a-methyl substituent would enhance potency by protecting the 20-ketone from metabolism. Ultimately, these authors prepared 9-fluoro-16a-methylprednisolone which was the first derivative of fluorocortisol with markedly increased anti-inflammatory activity that was devoid of mineralocorticoid activity. This latter fact supports the concept that it is the presence of 16a-substituents that prevents binding to the mineralocorticoid receptor. Dexamethasone has become Merck s principal marketed anti-inflammatory steroid. 

Between 1953 and 1962, many derivatives of the A -corticoids and the halogen-containing analogues (especially fluorinated compounds) were synthesized, and some became useful clinical agents. Studies with methylcorticoids revealed 2a-methyl derivatives to be inactive, whereas the 2a-methyl-9a-fluoro analogues had potent mineralocorticoid activity. Methyprednisolone (6a-methyl-11 (3,17,21-trihydroxypregna-1,4-diene-... 

A natural extension of corticoid research involved examination of compounds containing both a 9a-fluoro group and a double bond between positions 1 and 2. Triamcinolone (9-fluoro-11 (3, 16a, 17, 21-tetrahydroxypregna-1,4-diene-3,20-dione), introduced in 1958, combines the structural features of a A -corticoid and a 9a-fluoro corticoid (Fig. 33.10). As mentioned previously, the 9a-fluoro group increases the anti-inflammatory potency, but it also markedly increases the mineralocorticoid potency. This is undesirable if the drug is to be used internally for the treatment of rheumatoid arthritis. By inserting a 16a-hydroxy group into the molecule, one can decrease the mineralocorticoid activity. 

Flunisolide is an acetone ketal (acetonide) with a 6a-fluoro group and a free C-21 hydroxyl group. The acetonide decreases mineralocorticoid activity, and the 6a-fluoro group increases glucocorticoid activity. It is not a prodrug, because it has the free hydroxyl group at C-21. Flunisolide has approximately 20% of the receptor affinity as budesonide, and approximately 40% of the inhaled dose is systemically bioavailable. Flunisolide is quickly metabolized by CYP3A4 to the 6p-hydroxy metabolite, which has less than 1% of the activity of the parent compound. This,... 

Daxamathasone, 9a-fluora-I6a-methylpredniso-loue, 9a-fluoro-lip,I7,2I-trihydroxy-I6a-melhyl-pregna-l,4-diene-3,20-dione a synthetic pregnane derivative (see Steroids) which is highly antiinflammatory but has little mineralocorticoid activity. It is used to relieve arthritis. D. is synthesized from cortisol. 

---