In a continuing effort to minimize the systemic adverse effects of potent anti-inflammatory
steroids, a series of 16 alpha-alkoxycarbonyl-17-deoxyprednisolone derivatives: methyl (8a), ethyl (8b), isopropyl (8c), and benzyl (8d) 11 beta,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16 alpha-carboxylate, was synthesized and evaluated for their topical and local anti-inflammatory activities. In the acute
croton oil-induced ear
edema dose-response bioassay, the topical anti-inflammatory potencies of these
esters relative to
prednisolone, 1, were: 8a:1.0, 8b:1.3, 8c:4.0, 8a:4.7 and 1:1.0. The putative metabolite, 11 beta,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16 alpha-
carboxylic acid, 7, was inactive in this test. A seven day cotton pellet
granuloma bioassay was employed to study the local and systemic anti-inflammatory activities of these
steroids. The local anti-inflammatory potencies of these
esters relative to
prednisolone, 1, were 1.3, 1.5, 2.3, 2.5, and 1.0 for 8a, 8b, 8c, 8d, and 1, respectively. In this semi-chronic study, only
prednisolone exhibited significant untoward side effects, such as reduction in thymus weights, normal body
weight gain, and normal plasma
corticosterone levels. The increase in the topical and local potencies of these
steroid esters was consistent with the increase in their
1-octanol/
buffer partition coefficient. The ratio of local to systemic anti-inflammatory activity of 8c and 8d was four times that of
prednisolone. The effects of increasing the size of the
alkoxy group of these new
steroids on both topical and local anti-inflammatory activity and their concomitant decrease in untoward systemic effects were unequivocally demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)