Synthesis of (bis)sulfonic acid, (bis)benzamides as follicle-stimulating hormone (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 microM in the FSHR-cAMP assay was essentially inactive at 30 microM in the TSHR-cAMP assay.
Wrobel
Jay
J
Chemical Sciences, Wyeth Research, Inc, 500 Arcola Road, Collegeville, PA 19426, USA. wrobelj@war.wyeth.com
Green
Daniel
D
Jetter
James
J
Kao
Wenling
W
Rogers
John
J
Pérez
M Claudia
MC
Hardenburg
Jill
J
Deecher
Darlene C
DC
López
Francisco J
FJ
Arey
Brian J
BJ
Shen
Emily S
ES
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019281:Dimerization; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000037:antagonists & inhibitors*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011962:Receptors, FSH / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000037:antagonists & inhibitors / Q000235:genetics; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D013737:Testis / Q000166:cytology; D014162:Transfection; D014407:Tumor Cells, Cultured
D001549:Benzamides; D004965:Estrogen Antagonists; D011962:Receptors, FSH; D011989:Receptors, Thyrotropin; D013451:Sulfonic Acids; D011374:Progesterone; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP