Steroid acids derived from the biotransformation of the 17-ketol side- chain of corticosteroids have been identified in human and animal urine. The purpose of this investigation is to synthesize ester derivatives of steroid acids from potent corticosteroids and to evaluate the steroid as safer anti-inflammatory agents for prolonged use. The concept, antedrug, being formulated from the results of differences in anti-inflammatory potency of prototypes of the steroid acid derivatives depending on the routes of administration is that the derivatives possess anti- inflammatory activity per se, but upon entry into the circulatory system from the administration site, are hydrolyzed to inactive steroid acids. It is proposed to investigate the structure activity relationship, mechanism of action and pharmacokinetics of this new class of corticosteroids with metabolically labile group. New steroid acid esters will be synthesized and comprehensively evaluated as anti-inflammatory agents using the carrageenan-induced rat paw edema, croton oil-induced ear edema test and cotton pellet granuloma bioassay, with respect to various routes of administration. To further delineate the mode of action of the steroids, their effect on pituitary-adrenal function, glycogen deposition, and liberation of prostanoids and elastase will be studied. The metabolic rate of these steroids in rats will be investigated using radiolabeled compounds. Results of these studies will yield valuable insight into the structural characteristics for the maximum separation of local anti-inflammatory activity from systemic adverse effects and mode of action of these new corticosteroids with the promise of providing a solid rational basis for development of new potent anti-inflammatory steroids devoid of systemic side effects, which will therefore be more acceptable for use in the clinical environment.
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