Estradiol-16 alpha-carboxylic acid esters as locally active estrogens

We attempted to design analogues of estradiol to act as locally active estr ogens without significant systemic action. We synthesized a series of 16a-c arboxylic acid substituted steroids and their esters and tested their actio n in several assays of estrogenic action, including estrogen receptor (ER) binding, estrogenic potency in Ishikawa cells (human endometrial carcinoma) , rat uterine weight (systemic action), and mouse vaginal reductases (local action). All of the estradiol substituted carboxylic acids (formic, acetic and propionic acids) were devoid of estrogenic action. To the contrary, ma ny of the esters had marked estrogenic potency in the receptor and the Ishi kawa assays. The eaters of the 16 alpha -formic acid series had the highest ER affinity with little difference between the straight-chain alcohol este rs (from methyl to n-butyl). However, estrogenic action in the Ishikawa ass ay decreased precipitously with esters longer than the ethyl ester. This de crease correlated well with the increased rate of esterase hydrolysis of lo nger esters as determined in incubations with rat hepatic microsomes. The m ost promising candidates, the methyl, ethyl, and fluoroethyl esters of the formate series, were tested for systemic and local action in the in vivo mo dels. All three, especially the fluoroethyl ester, showed divergence betwee n systemic and local estrogenic action. These metabolically labile estrogen s will be extremely useful for the therapeutic treatment of the vaginal dys pareunia of menopause in women for whom systemic estrogens are contraindica ted.