Effect of SKI2670, a novel, orally active, non-peptide GnRH antagonist, on hypothalamic-pituitary-gonadal axis

Life Sciences
Seon Mi KimHun-Taek Kim

Abstract

Suppression of the hypothalamic-pituitary-gonadal axis has been widely utilized for the management of gonadal-hormone-dependent diseases such as endometriosis. Efforts to develop orally available gonadotropin-releasing hormone (GnRH) antagonists for the treatment of gonadal-hormone-dependent diseases led to the discovery of SKI2670, a novel non-peptide GnRH antagonist. The present study was undertaken to pharmacologically characterize SKI2670 in vitro and in vivo. We measured binding affinity and antagonistic activity of SKI2670 for the GnRH receptors. Immediate suppression of gonadotropins by single dosing of SKI2670 was examined in castrated monkeys. Subsequently, influence on gonadal hormones by prolonged administration of SKI2670 was assessed in naive female monkeys. To investigate in vivo efficacy of SKI2670, regression of ectopic implants by repeated administration of SKI2670 was examined in a rat endometriosis model. SKI2670 is a potent functional antagonist for the human GnRH receptor, with subnanomolar binding affinity. In castrated monkeys, single administration of SKI2670 lowered serum luteinizing hormone (LH) levels stronger with longer duration when compared to elagolix at equivalent doses. Moreover, repeated dosin...Continue Reading

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Citations

Sep 9, 2016·Journal of Medicinal Chemistry·Seon-Mi KimJeewoo Lee
Dec 14, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Feng-Ling TukunJo Klaveness
Jan 5, 2019·Clinical and Experimental Pharmacology & Physiology·Aleksandra Suszka-ŚwitekRyszard Wiaderkiewicz
Dec 22, 2020·The Journal of Clinical Endocrinology and Metabolism·Sungpil HanKyun-Seop Bae

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