Synthesis of (bis)Sulfonic acid, (bis)Benzamides as follicle-Stimulating hormone (FSH) antagonists Original Research Article

Screening efforts identified (bis)sulfonic acid, (bis)benzamides (1–3) as compounds that interact with the follicle stimulating-hormone receptor (FSHR) and inhibit FSH-stimulated cAMP accumulation with IC50 values in the low micromolar range. Structure–activity relationship studies using novel analogues of 1–3 revealed that two phenylsulfonic acid moieties were necessary for activity and that the carbon–carbon double bond of the stilbene sub-series was the optimum spacer connecting these groups. Selected analogues (2, 14, and 50) were also able to block FSHR-dependent estradiol production in rat primary ovarian granulosa cells and progesterone secretion in a clonal mouse adrenal Y1 cell line. IC50 values for these compounds in these assays were in the low micromolar range. Optimization of the benzoic acid side chains of 1–3 led to gains in selectivity versus activity at the thyroid stimulating hormone (TSH) receptor (TSHR). For instance, while stilbene (bis)sulfonic acid congener 2 was only 10-fold selective for FSHR over TSHR, analogue 50 with an IC50 value of 0.9 μM in the FSHR-cAMP assay was essentially inactive at 30 μM in the TSHR-cAMP assay.