Abstract
A variety of acyl derivatives based on the “antedrug” concept were synthesized to evaluate their biological activities, in vitro fate in human serum and examine pharmacokinetics in rats. Among the prepared compounds, acetyl and pivaloyl derivatives (8 and 9) showed strong to vasoconstrictive activity in human, exceeding that of dexamethasone. In rats, topical administration of the compound 8 significantly reduced oxazolone-induced ear edema compared to that of control. These activities were almost equal to that of prednisolone, however 9 did not show any suppression of the oxazolone-induced edema. The in vitro half-lives of 8 and 9 in human serum were 18.2 and 43.8 hours, respectively. Prednisolone and dexamethasone were extremely stable under the used conditions. When compound 8 was intravenously administrated to rats, its metabolites, 20(R)-methyl dexamethasonate (4) and carboxylic acid (18), were found in the systemic blood. The total body clearance of 8 was 1734 ml · hr−1 · kg−1, which was about 12 times larger than that of dexamethasone. On the other hand, 9 was found to be metabolized instantaneously to methyl prednisolonate (1) in systemic serum. Acetyl derivative 8 derived from dexamethasone may thus be useful as a topical steroid which offers the advantage of a low potential for systemic and local side effects.
