title: Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice.
abstract: TAK-385 (relugolix) is a novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist, which builds on previous work with non-peptide GnRH antagonist TAK-013. TAK-385 possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared with TAK-013. Both TAK-385 and TAK-013 have low affinity for the rat GnRH receptor, making them difficult to evaluate in rodent models. Here we report the human GnRH receptor knock-in mouse as a humanized model to investigate pharmacological properties of these compounds on gonadal function. Twice-daily oral administration of TAK-013 (10mg/kg) for 4 weeks decreased the weights of testes and ventral prostate in male knock-in mice but not in male wild-type mice, demonstrating the validity of this model to evaluate antagonists for the human GnRH receptor. The same dose of TAK-385 also reduced the prostate weight to castrate levels in male knock-in mice. In female knock-in mice, twice-daily oral administration of TAK-385 (100mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomized levels and downregulated GnRH receptor mRNA in the pituitary after 4 weeks. Gonadal function of TAK-385-treated knock-in mice began to recover after 5 days and almost completely recovered within 14 days after drug withdrawal in both sexes. Our findings demonstrate that TAK-385 acts as an antagonist for human GnRH receptor in vivo and daily oral administration potently, continuously and reversibly suppresses the hypothalamic-pituitary-gonadal axis. TAK-385 may provide useful therapeutic interventions in hormone-dependent diseases including endometriosis, uterine fibroids and prostate cancer.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Daisuke
authors: D
authors: Nakata
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Tsuneo
authors: T
authors: Masaki
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Akira
authors: A
authors: Tanaka
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Mie
authors: M
authors: Yoshimatsu
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Yumiko
authors: Y
authors: Akinaga
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Mari
authors: M
authors: Asada
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Reiko
authors: R
authors: Sasada
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Michiyasu
authors: M
authors: Takeyama
authors: CMC Center, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
authors: Kazuhiro
authors: K
authors: Miwa
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tatsuya.watanabe@takeda.com.
authors: Tatsuya
authors: T
authors: Watanabe
authors: CMC Center, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
authors: Masami
authors: M
authors: Kusaka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015507:Drugs, Investigational / Q000494:pharmacology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006066:Gonads / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000235:genetics; D013739:Testosterone / Q000097:blood
chemical_list: D015507:Drugs, Investigational; C484844:GNRHR protein, human; D010671:Phenylurea Compounds; D011744:Pyrimidinones; D012333:RNA, Messenger; D011966:Receptors, LHRH; C561634:relugolix; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone
keywords: Endometriosis; GnRH antagonist; Human GnRH receptor knock-in mouse; Prostate cancer; TAK-013 (PubChem CID: 3038517); TAK-385; TAK-385 (PubChem CID: 10348973); Uterine fibroids