Pharmacological evaluation of five novel dexamethasone heneicosoic (21) acid derivatives

Five novel dexamethasone 21-oic acid derivatives (DM-I, II, IV, V and VI) were prepared from dexamethasone in accordance with the antedrug concept and their local anti-inflammatory activities and systemic untoward effects were evaluated through steroid receptor binding study, cotton pellet granuloma bioassay and acute pharmacological studies. The acetonide derivatives, DM-V and DM-VI, were found to possess much stronger affinities to glucocorticoid receptors than the acid ester derivatives, DM-I and DM-II, in vitro. In in vivo experiments, locally applied DM-V and DM-VI exerted potent inhibitory activity against granuloma formation; DM-I and DM-II also produced moderate granuloma inhibitory activity in spite of their weak affinity to the receptors. DM-II, DM-V and DM-VI manifested less systemic effects than dexamethasone, prednisolone and DM-I, such as thymus involution, suppression of plasma corticosterone and gluconeogenesis in the liver. Among the five compounds, DM-V could be exemplified as a potentially useful antedrug for topical or local application, since it has anti-inflammatory potency approaching that of the more traditional steroid prednisolone, but it does not have the systemic adverse effects.