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

Abstract

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 IC 50 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. IC 50 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 IC 50 value of 0.9 μM in the FSHR-cAMP assay was essentially inactive at 30 μM in the TSHR-cAMP assay.