Metabolic inactivation ketonic

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. 

Structural modifications were carried out in some classes of steroids in order to block another known route of metabolic inactivation, namely, the reduction of the A -3-ketone system. The structural changes, such as 2a-methylation or 6a-methylation were aimed to slow down the rate of... 

Generally, inversion of the 15-hydroxy group to the 15-epi configuration results in an essential loss of activity (1131. as does oxidation of this group to a ketone which is the major product of metabolic inactivation. 

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