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Identification and Characterization of a Selective, Nonpeptide Follicle-Stimulating Hormone Receptor Antagonist

Women’s Health Research Institute and Medicinal Chemistry, Department of Chemical Sciences, Wyeth Research, Collegeville, Pennsylvania 19680

Address all correspondence and requests for reprints to: Darlene C. Deecher, Women’s Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19680. E-mail: deeched{at}wyeth.com.

The glycoprotein hormones (LH, FSH, and TSH) are critical to the maintenance of physiological homeostasis and control of reproduction. However, despite an obvious utility for synthetic pharmacological agents, there are few reports of selective, nonpeptide agonists or antagonists to receptors for these hormones. We have identified and characterized a novel synthetic molecule capable of inhibiting the action of FSH. This compound, 7-{4-[Bis-(2-carbamoyl-ethyl)-amino]-6-chloro-(1,3,5)-triazin-2-ylamino)-4-hydroxy-3-(4-methoxy-phenylazo)-naphthalene}-2-sulfonic acid, sodium salt (compound 1), is a selective, noncompetitive inhibitor of the human (h) and rat (r) FSH receptors (FSHRs). Compound 1 selectively inhibited binding of [¹²⁵I]hFSH with an IC₅₀ value of 5.4 ± 2.3 µM. Radioligand-binding assays were performed using the baculovirus expressed extracellular domain of hFSHR (BV-tFSHR) to demonstrate site-specific interaction. Compound 1 competed for [¹²⁵I]hFSH binding to BV-tFSHR with an IC₅₀ value of 10 ± 2.8 µM. Functionally, compound 1 inhibited hFSH-induced cAMP accumulation and steroidogenesis in vitro with an IC₅₀ value of 3 ± 0.6 µM. Competition of compound 1 for binding to other glycoprotein hormone receptors and other G protein-coupled receptors demonstrated select activity for FHSRs. Compound 1 inhibited ovulation in immature and cycling adult rats. These data provide proof of concept that selective, small molecule antagonists can be designed for glycoprotein hormone receptors.

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