Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16 alpha, 17 alpha-acetal-substituted glucocorticoids.

The affinity for the glucocorticoid receptor in rat skeletal muscle of some glucocorticoids with a new type of 16 alpha, 17 alpha-acetal substituent has been estimated and correlated to the glucocorticoid activities in three in vivo systems in rats. Budesonide (an approximately 1:1 mixture of the C(22) epimers of 11 beta, 21-dihydroxy-16 alpha, 17 alpha-[(22R,S)-propylmethylenedioxy]-pregna-1,4-diene-3,20-dione) and the isolated (22R)- and (22S)-epimers bound to the same binding site as the potent glucocorticoids dexamethasone (DEX) or triamcinolone 16 alpha, 17 alpha-acetonide (TA), but with even higher affinity than DEX or TA, despite the lack of a 9 alpha-fluoro atom in budesonide and its epimers. The (22R)-epimer was twice as active as the (22S)-epimer, 4 times more active than TA, and 14 times more active than DEX. The introduction of a 9 alpha-fluoro atom slightly decreased the binding affinity of the (22R)-epimer of budesonide, in contrast to the positive effect of 9 alpha-fluorination of, e.g., 16 alpha, 17 alpha-acetonides. The negative influence of 9 alpha-fluorination of the (22R)-epimer was partially reversed in the 6 alpha, 9 alpha-difluorinated (22R)-epimer. Nevertheless, the fluorinated compounds were more active than DEX and TA (8 and 11 times more active than DEX, and 2 and 3 times more active than TA, in case of the 9 alpha-fluoro- and 6 alpha, 9 alpha-difluoro-derivatives of the (22R)-epimer, respectively). Budesonide is metabolized mainly to 16 alpha-hydroxyprednisolone (11 beta, 16 alpha, 17 alpha, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione) and 6 beta-hydroxy-budesonide. Both metabolites were very weak competitors for the ligand-binding sites on the receptor (3% and 6% of the affinity of DEX, respectively). The affinity for the receptor in vitro was closely correlated to the topical glucocorticoid activity in vivo for the 12 steroids compared (r = 0.98; R = 0.98), which supports the contention that in vitro tests for receptor affinity are useful when screening for agonists among steroids with the present type of structures. The results on receptor-ligand interaction are in accordance with X-ray crystallographic data available for some steroids.