title: Steroidal anti-inflammatory antedrugs: synthesis and pharmacological evaluation of 16 alpha-alkoxycarbonyl-17-deoxyprednisolone derivatives.
abstract: 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)
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D003345:Corticosterone / Q000097:blood; D003436:Croton Oil; D004427:Ear Diseases / Q000188:drug therapy; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D003368:Gossypium; D006099:Granuloma / Q000188:drug therapy / Q000209:etiology; D008297:Male; D011239:Prednisolone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C096296:16-benzyloxycarbonyl-17-deoxyprednisolone; C096295:16-isopropoxycarbonyl-17-deoxyprednisolone; D000893:Anti-Inflammatory Agents; D003436:Croton Oil; D011239:Prednisolone; D003345:Corticosterone