title: Synthesis and antiinflammatory activity of novel 12 beta-substituted analogues of betamethasone.
abstract: A series of 9 alpha-halo-12 beta-hydroxy and 12 beta-acyloxy analogues of betamethasone 17,21-dipropionate were synthesized and tested for topical antiinflammatory potency in the croton oil ear assay. The compounds were assayed for systemic absorption in the contralateral ear assay, in which it was found that 12 beta-hydroxy analogues 9, 13, and 15 were all absorbed but the corresponding 12 beta-esters 11a-e, 14, and 16 were not. On repeated high-dose applications to the mouse ear, there was no evidence of systemic absorption of any 12 beta-propionate ester as gauged by thymus weights (thymic involution) and plasma cortisol levels (adrenal suppression). Results of limited SAR studies showed that topical antiinflammatory activity and systemic absorption were not greatly influenced by the 9 alpha-halogen but were largely dependent on the polarity and size of the 12 substituent. While the optimal compounds 14 and 16 were less topically active than the controls beta- and beclomethasone dipropionate, unlike the controls, they displayed no systemic effects, even after repeated high-dose applications. Surprisingly, propionate 14 was devoid of atrophogenic activity.
authors.affiliation: Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, California 94025.
authors.forename: M A
authors.initials: MA
authors.lastname: Avery
authors.forename: G
authors.initials: G
authors.lastname: Detre
authors.forename: D
authors.initials: D
authors.lastname: Yasuda
authors.forename: W R
authors.initials: WR
authors.lastname: Chao
authors.forename: M
authors.initials: M
authors.lastname: Tanabe
authors.forename: D
authors.initials: D
authors.lastname: Crowe
authors.forename: R
authors.initials: R
authors.lastname: Peters
authors.forename: W K
authors.initials: WK
authors.lastname: Chong
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D001623:Betamethasone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D012016:Reference Values; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000033:anatomy & histology / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007202:Indicators and Reagents; D001623:Betamethasone; D006854:Hydrocortisone