title: 6 alpha-Fluoro- and 6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione: synthesis and evaluation of activity and kinetics of their C-22 epimers.
abstract: It is generally accepted that the anti-inflammatory effect of glucocorticosteroids cannot be separated from their adverse effects at the receptor level. However, modification of the pharmacokinetics through structural alterations could provide steroids with a better therapeutic index than those currently used. Thus, new 16 alpha,17 alpha-acetals between butyraldehyde and 6 alpha-fluoro- or 6 alpha,9 alpha-difluoro-16 alpha-hydroxycortisol were synthesized and studied. Acetalization of the corresponding 16 alpha,17 alpha-diols or transacetalization of their 16 alpha,17 alpha-acetonides in dioxane produced mixtures of C-22 epimers, which were resolved by preparative chromatography. Alternatively, an efficient method was used to produce the 22R-epimer stereoselectively through performing the acetalization and transacetalization in a hydrocarbon with an inert material present. The C-22 configuration of (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione was unambiguously established by single crystal X-ray diffraction. The present compounds, especially the 22R-epimer just mentioned, bind to the rat thymus glucocorticoid receptor with high potency. The C-22 epimers of the 6 alpha,9 alpha-difluoro derivatives showed a 10-fold higher biotransformation rate than the budesonide 22R-epimer when incubated with human liver S9 subcellular fraction. The high receptor affinity in combination with the high biotransformation rate indicates that (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione may be an improved 16 alpha,17 alpha-acetal glucocorticosteroid for therapy of inflammatory diseases, in which the mucous membranes are involved, such as those in the intestinal tract as well in the respiratory tract.
authors.affiliation: Department of Medicinal Chemistry, Astra Draco AB, Lund, Sweden.
authors.forename: B A
authors.initials: BA
authors.lastname: Thalén
authors.forename: B I
authors.initials: BI
authors.lastname: Axelsson
authors.forename: P H
authors.initials: PH
authors.lastname: Andersson
authors.forename: R L
authors.initials: RL
authors.lastname: Brattsand
authors.forename: B
authors.initials: B
authors.lastname: Nylander
authors.forename: L I
authors.initials: LI
authors.lastname: Wickström
mesh_terms: D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D004060:Diflucortolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005938:Glucocorticoids / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: C110466:6,9-difluoro-11,21-dihydroxy-16,17-propylmethylenedioxypregn-4-ene-3,20-dione; C110465:6-fluoro-11,21-dihydroxy-16,17-propylmethylenedioxypregn-4-ene-3,20-dione; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D004060:Diflucortolone