| Abstract
| - We attempted to design analogues of estradiol to act as locally active estrogens withoutsignificant systemic action. We synthesized a series of 16α-carboxylic acid substituted steroidsand their esters and tested their action in several assays of estrogenic action, including estrogenreceptor (ER) binding, estrogenic potency in Ishikawa cells (human endometrial carcinoma),rat uterine weight (systemic action), and mouse vaginal reductases (local action). All of theestradiol substituted carboxylic acids (formic, acetic and propionic acids) were devoid ofestrogenic action. To the contrary, many of the esters had marked estrogenic potency in thereceptor and the Ishikawa assays. The esters of the 16α-formic acid series had the highest ERaffinity with little difference between the straight-chain alcohol esters (from methyl to n-butyl).However, estrogenic action in the Ishikawa assay decreased precipitously with esters longerthan the ethyl ester. This decrease correlated well with the increased rate of esterase hydrolysisof longer esters as determined in incubations with rat hepatic microsomes. The most promisingcandidates, the methyl, ethyl, and fluoroethyl esters of the formate series, were tested forsystemic and local action in the in vivo models. All three, especially the fluoroethyl ester, showeddivergence between systemic and local estrogenic action. These metabolically labile estrogenswill be extremely useful for the therapeutic treatment of the vaginal dyspareunia of menopausein women for whom systemic estrogens are contraindicated.
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