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Sufugolix (INNTooltip International Nonproprietary Name, BANTooltip British Approved Name) (developmental code name TAK-013) is a non-peptide, orally-active, selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (IC50Tooltip Half-maximal inhibitory concentration = 0.1 and 0.06 nM for affinity and in vitro inhibition, respectively).[1] It was under development by Takeda for the treatment of endometriosis and uterine leiomyoma and reached phase II clinical trials for both of these indications, but was subsequently discontinued.[2][3] It seems to have been supplanted by relugolix (TAK-385), which is also under development by Takeda for the treatment of these conditions and has a more favorable drug profile (including reduced cytochrome P450 inhibition and improved in vivo GnRHR antagonistic activity) in comparison.[4]

Oral administration of sufugolix at a dose of 30 mg/kg to castrated male cynomolgus monkeys resulted in nearly complete suppression of luteinizing hormone levels.[1] The duration of action was more than 24 hours, indicating a long elimination half-life of the drug.[1] The suppressive effects of sufugolix on gonadotropin and sex hormone levels are rapidly reversible with discontinuation.[5]

Unlike various other GnRHR antagonists, sufugolix has been elucidated to be a non-competitive or insurmountable/trapping antagonist of the GnRHR rather than a competitive antagonist.[6][7]

See also

References

  1. ^ a b c Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, et al. (January 2003). "Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor". Journal of Medicinal Chemistry. 46 (1): 113–124. doi:10.1021/jm020180i. PMID 12502365.
  2. ^ Lanier MC, Feher M, Ashweek NJ, Loweth CJ, Rueter JK, Slee DH, et al. (August 2007). "Selection, synthesis, and structure-activity relationship of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists". Bioorganic & Medicinal Chemistry. 15 (16): 5590–5603. doi:10.1016/j.bmc.2007.05.029. PMID 17561404.
  3. ^ "Sufugolix - Takeda". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 2016-03-04. Retrieved 2015-10-12.
  4. ^ Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, et al. (July 2011). "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 receptor". Journal of Medicinal Chemistry. 54 (14): 4998–5012. doi:10.1021/jm200216q. PMID 21657270.
  5. ^ Hara T, Araki H, Kusaka M, Harada M, Cho N, Suzuki N, et al. (April 2003). "Suppression of a pituitary-ovarian axis by chronic oral administration of a novel nonpeptide gonadotropin-releasing hormone antagonist, TAK-013, in cynomolgus monkeys". The Journal of Clinical Endocrinology and Metabolism. 88 (4): 1697–1704. doi:10.1210/jc.2002-021065. PMID 12679460.
  6. ^ Kohout TA, Xie Q, Reijmers S, Finn KJ, Guo Z, Zhu YF, Struthers RS (August 2007). "Trapping of a nonpeptide ligand by the extracellular domains of the gonadotropin-releasing hormone receptor results in insurmountable antagonism". Molecular Pharmacology. 72 (2): 238–247. doi:10.1124/mol.107.035535. PMID 17409285. S2CID 23980337.
  7. ^ Szkudlinski MW (August 2007). "Challenges and opportunities of trapping ligands". Molecular Pharmacology. 72 (2): 231–234. doi:10.1124/mol.107.038208. PMID 17522183. S2CID 25807899.

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