This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hara, T. Articles by Fujino, M. Search for Related Content PubMed PubMed Citation Articles by Hara, T. Articles by Fujino, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ESTRADIOL MENOTROPINS PROGESTERONE

Suppression of a Pituitary-Ovarian Axis by Chronic Oral Administration of a Novel Nonpeptide Gonadotropin-Releasing Hormone Antagonist, TAK-013, in Cynomolgus Monkeys

Pharmaceutical Research Division (T.H., H.A., M.K., M.H., N.C., N.S., M.F.) and Strategic Product Planning Department (S.F., M.F.), Takeda Chemical Industries, Ltd., Osaka 532-8686, Japan

Address all correspondence and requests for reprints to: Takahito Hara, M.D., Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., 17-85 Jusohonmachi 2-chome Yodogawa-ku, Osaka 532-8686, Japan. E-mail: Hara_Takahito{at}takeda.co.jp.

TAK-013 is a novel nonpeptide and orally active GnRH antagonist. We first examined the effect of TAK-013 on GnRH-stimulated LH release using primary-cultured pituitary cells of cynomolgus monkeys. TAK-013 suppressed LH release to below basal levels at concentrations higher than 100 nM with the IC₅₀ value of 36 nM. Next, we examined the effect of chronic oral administration of TAK-013 on serum hormone levels in regularly cycling female cynomolgus monkeys. TAK-013 administered at 90 mg/kg·d (30 mg/kg 3 times daily) for approximately 80 d continued to suppress LH, estradiol, and progesterone, but not FSH. The suppressive effect was reversible, in that normal profiles of sex steroids were observed immediately after discontinuation of the TAK-013 treatment. Interestingly, the suppressive effect of TAK-013 was not observed in marmoset monkeys. In summary, TAK-013 by oral administration suppresses a pituitary-ovarian axis continuously and reversibly in cynomolgus monkeys. Considering that TAK-013 has more potent antagonistic properties for human GnRH receptor than for monkey receptor, our data suggest that TAK-013 would be effective for reproductive disorders such as endometriosis and uterine leiomyoma and useful for assisted reproductive technology procedures.

This article has been cited by other articles:

				T. A. Kohout, Q. Xie, S. Reijmers, K. J. Finn, Z. Guo, Y.-F. Zhu, and R. S. Struthers Trapping of a Nonpeptide Ligand by the Extracellular Domains of the Gonadotropin-Releasing Hormone Receptor Results in Insurmountable Antagonism Mol. Pharmacol., August 1, 2007; 72(2): 238 - 247. [Abstract] [Full Text] [PDF]

				R. S. Struthers, Q. Xie, S. K. Sullivan, G. J. Reinhart, T. A. Kohout, Y.-F. Zhu, C. Chen, X.-J. Liu, N. Ling, W. Yang, et al. Pharmacological Characterization of a Novel Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor, NBI-42902 Endocrinology, February 1, 2007; 148(2): 857 - 867. [Abstract] [Full Text] [PDF]

				B.C. Tarlatzis, B.C. Fauser, E.M. Kolibianakis, K. Diedrich, P. Devroey, and , On Behalf of the Brussels GnRH Antagonist Consen GnRH antagonists in ovarian stimulation for IVF Hum. Reprod. Update, July 1, 2006; 12(4): 333 - 340. [Abstract] [Full Text] [PDF]