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Sufugolix
Clinical data
Other names	TAK-013
Routes of; administration	By mouth
Drug class	GnRH modulator; GnRH antagonist; Antigonadotropin
ATC code	None;
Identifiers
	IUPAC name 1-[4-[5-[[benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea;
CAS Number	308831-61-0;
PubChem CID	3038517;
ChemSpider	2302081;
UNII	56S17Z6X9M;
CompTox Dashboard (EPA)	DTXSID40184893 ;
Chemical and physical data
Formula	C36H31F2N5O4S
Molar mass	667.73 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1;
	InChI InChI=1S/C36H31F2N5O4S/c1-41(20-23-10-5-3-6-11-23)21-28-31-33(44)43(26-12-7-4-8-13-26)36(46)42(22-27-29(37)14-9-15-30(27)38)34(31)48-32(28)24-16-18-25(19-17-24)39-35(45)40-47-2/h3-19H,20-22H2,1-2H3,(H2,39,40,45); Key:UCQSBGOFELXYIN-UHFFFAOYSA-N;

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]

References

^ ^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.
^ 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.
^ "Sufugolix - Takeda". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 2016-03-04. Retrieved 2015-10-12.
^ 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.
^ 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.
^ 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.
^ 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.