title: Effect of SKI2670, a novel, orally active, non-peptide GnRH antagonist, on hypothalamic-pituitary-gonadal axis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 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.
  
  
  CONCLUSIONS
  Our 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.
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea.
authors: Seon Mi
authors: SM
authors: Kim
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea.
authors: Taekyung
authors: T
authors: Yoo
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea.
authors: So Young
authors: SY
authors: Lee
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea.
authors: Eun Jeong
authors: EJ
authors: Kim
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea.
authors: Soo Min
authors: SM
authors: Lee
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea.
authors: Min Hee
authors: MH
authors: Lee
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea.
authors: Min Young
authors: MY
authors: Han
authors: Division of Molecular Biology, College of Pharmacy and Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Seung-Hyun
authors: SH
authors: Jung
authors: Division of Molecular Biology, College of Pharmacy and Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Jung-Hye
authors: JH
authors: Choi
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea.
authors: Keun Ho
authors: KH
authors: Ryu
authors: Life Science R&D Center, SK Chemicals Co. Ltd., Seongnam 463-400, Gyeonggi-do, Republic of Korea. Electronic address: huntaekkim@sk.com.
authors: Hun-Taek
authors: HT
authors: Kim
mesh_terms: D000818:Animals; D004715:Endometriosis / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D042341:Gonadal Hormones / Q000097:blood / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006062:Gonadotropins / Q000097:blood / Q000378:metabolism; D057809:HEK293 Cells; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D042341:Gonadal Hormones; D006062:Gonadotropins; D006727:Hormone Antagonists; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone
keywords: Endometriosis; Gonadal-hormone-dependent disease; Gonadotropin-releasing hormone (GnRH); SKI2670