Sufugolix Explained

Sufugolix (developmental code name TAK-013) is a non-peptide, orally-active, selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (= 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. The duration of action was more than 24 hours, indicating a long elimination half-life of the drug. 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

• Gonadotropin-releasing hormone receptor § Antagonists

External links

• Sufugolix - AdisInsight

Notes and References

1. Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M . 6 . 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 . January 2003 . 12502365 . 10.1021/jm020180i .
2. Lanier MC, Feher M, Ashweek NJ, Loweth CJ, Rueter JK, Slee DH, Williams JP, Zhu YF, Sullivan SK, Brown MS . 6 . 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 . August 2007 . 17561404 . 10.1016/j.bmc.2007.05.029 .
3. Web site: Sufugolix - Takeda . AdisInsight . Springer Nature Switzerland AG . 2015-10-12 . 2016-03-04 . https://web.archive.org/web/20160304193149/http://adisinsight.springer.com/drugs/800017215 . live .
4. Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T . 6 . Discovery of 1--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 . July 2011 . 21657270 . 10.1021/jm200216q .
5. Hara T, Araki H, Kusaka M, Harada M, Cho N, Suzuki N, Furuya S, Fujino M . 6 . 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 . April 2003 . 12679460 . 10.1210/jc.2002-021065 . free .
6. Kohout TA, Xie Q, Reijmers S, Finn KJ, Guo Z, Zhu YF, Struthers RS . 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 . August 2007 . 17409285 . 10.1124/mol.107.035535 . 23980337 .
7. Szkudlinski MW . Challenges and opportunities of trapping ligands . Molecular Pharmacology . 72 . 2 . 231–234 . August 2007 . 17522183 . 10.1124/mol.107.038208 . 25807899 .