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

Kim SM, Seon Mi Kim, Taekyung Yoo, Tae-Kyung Yoo, Yoo T, So Young Lee, Lee SY, Eun Jeong Kim, Kim EJ, Soo Min Lee, Lee SM, Min Hee Lee, Lee MH, Min Han, Min Young Han, Han MY, Seung-Hyun Jung, Jung SH, Jung‐Hye Choi, Jung-Hye Choi, Ryu KH, Keun Ho Ryu, Hun‐Taek Kim, Hun-Taek Kim, Kim HT
Life sciences · 2015 · vol. 139 , pp. 166–174 · doi:10.1016/j.lfs.2015.08.016 · PMID:26321528 · W1120214604
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This paper investigates the effects of SKI2670, a new oral non-peptide GnRH antagonist, on the hypothalamic-pituitary-gonadal axis in preclinical models.

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Abstract

AimsSuppression 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.Main methodsWe 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.Key findingsSKI2670 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 dosing of SKI2670 suppressed serum levels of gonadotropins and gonadal hormones in intact female monkeys while elagolix suppressed serum LH levels only. Finally, it exhibited regressive effects on ectopic implants in a rat endometriosis model without bone loss.SignificanceOur findings demonstrate robust GnRH antagonistic efficacy of SKI2670 in animal models, suggesting that SKI2670-induced suppression of the hypothalamic-pituitary-gonadal axis may be beneficial for the treatment of gonadal-hormone-dependent diseases such as endometriosis in humans.

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Condition tags

endometriosis

MeSH descriptors

Gonadotropin-Releasing Hormone Hormone Antagonists Receptors, LHRH Animals Endometriosis Endometriosis Endometriosis Female Gonadal Hormones Gonadal Hormones Gonadal Hormones Gonadotropin-Releasing Hormone Gonadotropins Gonadotropins Gonadotropins HEK293 Cells Hormone Antagonists Hormone Antagonists Hormone Antagonists Humans

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