Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 723, Issue -, Pages 167-174Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2013.12.001
Keywords
GnRH antagonist; Human GnRH receptor knock-in mouse; Endometriosis; Uterine fibroids; Prostate cancer; TAK-385
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Funding
- Millennium: The Takeda Oncology Company
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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 TALK-385 and TALK-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 TALK-013 (10 mg/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 (100 mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomizecl 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 clays 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. (C) 2013 Elsevier B.V. All rights reserved
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