The effect of side chain structure on the biochemical and therapeutic properties of intra-articular dexamethasone 21-esters.
The prolonged anti-rheumatic effects produced by some higher 21-esters of intra-articular corticosteroids have been ascribed to their low aqueous solubility or, alternatively, to their slow release of free (21-OH) steroid in the inflamed synovium. Experiments were designed to test this hypothesis. Twelve 21-carboxyl esters of dexamethasone and [3H]dexamethasone were prepared. Their side-chain structures were chosen to provide systematic steric hindrance of the scissile bond. Four dexamethasone/[3H]dexamethasone 21-carbamates were also prepared. When incubated with a 10% (w/v) homogenate of rabbit synovial tissue, esters providing steric hindrance, e.g. t-butylacetate, were more slowly hydrolysed than those which were linear, e.g. n-hexanoate, or cyclic e.g. cyclohexane acetate. Carbamate esters remained unhydrolysed during 24 hours' incubation. The partition coefficients of these compounds, derived using reversed-phase thin-layer chromatography and hydrophobic fragmental constants, were not correlated with their hydrolysis rates. Isomeric 21-substituents had similar partition coefficients. The affinity of the isomers, dexamethasone n-hexanoate and dexamethasone t-butylacetate, for the glucocorticoid receptor of mouse fibroblast cytosol, was determined by a competitive binding assay using [3H]triamcinolone acetonide. Dexamethasone t-butylacetate had 1/10 binding affinity relative to that of dexamethasone. Dexamethasone n-hexanoate was inactive. The therapeutic activities of dexamethasone n-hexanoate and dexamethasone t-butylacetate were compared at a single dose (2 mg), injected into experimentally-arthritic rabbit knee joints. These preparations reduced the swelling and histopathological changes in the treated joints by the same extent, indicating that the local anti-rheumatic activity of corticosteroid 21-esters is unrelated to their hydrolysis rates in vitro.
D000818:Animals; D001168:Arthritis / Q000188:drug therapy*; D001667:Binding, Competitive; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D004952:Esters; D006868:Hydrolysis; D007739:L Cells; D011817:Rabbits; D012995:Solubility; D013329:Structure-Activity Relationship; D014221:Triamcinolone / Q000378:metabolism
D004952:Esters; D014221:Triamcinolone; D003907:Dexamethasone