Estradiol-16α-carboxylic Acid Esters as Locally Active Estrogens

Abstract

We attempted to design analogues of estradiol to act as locally active estrogens without significant systemic action. We synthesized a series of 16alpha-carboxylic acid substituted steroids and their esters and tested their action 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, many of the esters had marked estrogenic potency in the receptor and the Ishikawa assays. The esters of the 16alpha-formic acid series had the highest ER affinity 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 longer than the ethyl ester. This decrease correlated well with the increased rate of esterase hydrolysis of longer esters as determined in incubations with rat hepatic microsomes. The most promising candidates, the methyl, ethyl, and fluoroethyl esters of the formate series, were tested for systemic and local action in the in vivo models. All three, especially the fluoroethyl ester, showed divergence between systemic and local estrogenic action. These metabolically labile estrogens will be extremely useful for the therapeutic treatment of the vaginal dyspareunia of menopause in women for whom systemic estrogens are contraindicated.

Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator

“…Twenty nanograms of E 2 is a relatively low dose, given that 5 ng E 2 is the lowest dose that consistently produces statistically significant uterotrophic stimulation (3). As shown in Fig.…”

“…Recently, we synthesized an unusual compound that has the properties of a SERM, but is devoid of their characteristic long-chain and polar substituents. We had been synthesizing novel families of locally active "soft" estrogens, for treatment of vaginal dyspareunia associated with menopause or antiestrogen therapy (3,4). These compounds are esters of carboxylic acid analogs of estradiol (E 2 ), and the esters are ER ligands capable of estrogenic stimulation, whereas the parent, charged carboxylates, are not.…”

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

“…[52] Compound 5 was then benzylated to obtain a 3-O-benzylestrone intermediate, which was then alkylated at position 16 through enolization by following a modified published procedure on a similar estrone derivative to give the 3-O-benzyl-protected ethyl ester 6 in an overall yield of 95 % (Scheme 1). [57] A new chiral centre at position 16 was generated during the formation of 6, and the resulting diastereomeric mixture was carried through the synthetic route described. The ratio of diastereomers at position 16 was 75:25, as determined by 1 H NMR spectroscopy, and the major product was shown to have the 16b configuration.…”

Retrometabolism‐Based Drug Design and Targeting

“…Along these lines, a series of estradiol-16a-carboxylic acid esters (69, Fig. 19) were synthesized and examined first [248]. Whereas, none of the acids (69, R ¼ H, m ¼ 0, 1, 2) showed significant estrogen receptor binding, the esters did.…”