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

• Published in: Bioorganic & medicinal chemistry Vol. 10; no. 3; pp. 639 - 656
• Main Authors: Wrobel, Jay, Green, Daniel, Jetter, James, Kao, Wenling, Rogers, John, Claudia Pérez, M, Hardenburg, Jill, Deecher, Darlene C, López, Francisco J, Arey, Brian J, Shen, Emily S
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2002; Elsevier Science
• Subjects: Animals; Benzamides - chemical synthesis; Benzamides - pharmacology; Biological and medical sciences; Birth control; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - biosynthesis; Dimerization; Estrogen Antagonists - chemical synthesis; Estrogen Antagonists - pharmacology; Female; Follicle Stimulating Hormone - antagonists & inhibitors; Granulosa Cells - drug effects; Granulosa Cells - metabolism; Gynecology. Andrology. Obstetrics; Humans; Inhibitory Concentration 50; Male; Medical sciences; Mice; Other methods of contraception. Sterilization; Progesterone - antagonists & inhibitors; Progesterone - biosynthesis; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, FSH - antagonists & inhibitors; Receptors, FSH - genetics; Receptors, FSH - metabolism; Receptors, Thyrotropin - antagonists & inhibitors; Receptors, Thyrotropin - genetics; Structure-Activity Relationship; Sulfonic Acids - chemical synthesis; Sulfonic Acids - pharmacology; Testis - cytology; Transfection; Tumor Cells, Cultured; Nitro compound; Sulfonamide; Selectivity; Morpholine derivatives; In vitro; Stilbene derivatives; Organic sulfide; Sulfonate; Adenohypophyseal hormone; Structure activity relation; Carboxamide; Benzenic compound; Aromatic compound; Contraceptive; Antagonist; Chemical synthesis; Follicle stimulating hormone; Oxygen nitrogen heterocycle
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00324-8

Novel (bis)sulfonic acid, (bis)benzamides were designed, synthesized, and evaluated as FSH antagonists. 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.