Relugolix (TAK-385)

TAK-385 is an orally bioavailable gonadotropin-releasing hormone receptor (GnRHR) antagonist (IC_50s = 0.33 and 0.32 nM for the human and monkey receptors, respectively).¹ It is selective for these receptors over the rat GnRHR receptor (IC₅₀ = 9,800 nM), as well as a panel of 134 enzymes and receptors at 10 ?M. TAK-385 is 95-fold more potent at inhibiting GnRH-induced arachidonic acid release in CHO cells expressing human GnRHR compared with those expressing monkey GnRHR. It decreases testis, ventral prostate, ovary, and uterus weight in human GNRHR knock-in mice when administered at doses ranging from 3 to 200 mg/kg per day for 28 days.² TAK-385 (1 and 3 mg/kg) also decreases plasma luteinizing hormone levels in castrated cynomolgus monkeys.¹

1.Miwa, K., Hitaka, T., Imada, T., et al.Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptorJ. Med. Chem.54(14)4998-5012(2011) 2.Nakata, D., Masaki, T., Tanaka, A., et al.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 miceEur. J. Pharmacol.723167-174(2014)