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

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