Sufugolix

{{Short description|Chemical compound}} {{Drugbox | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = 1-[4-[5-<nowiki>[[</nowiki>benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea | image = Sufugolix.svg | image_class = skin-invert-image | width = 250px

| C=36 | H=31 | F=2 | N=5 | O=4 | S=1 | SMILES = CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1 | StdInChI = 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) | StdInChIKey = UCQSBGOFELXYIN-UHFFFAOYSA-N }}

'''Sufugolix''' ({{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}) (developmental code name '''TAK-013''') is a non-peptide, orally-active, selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) ({{abbrlink|IC<sub>50</sub>|Half-maximal inhibitory concentration}} = 0.1 and 0.06 nM for affinity and ''in vitro'' inhibition, respectively).<ref name="pmid12502365">{{Cite journal |display-authors=6 |vauthors=Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M |date=January 2003 |title=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=Journal of Medicinal Chemistry |volume=46 |issue=1 |pages=113–124 |doi=10.1021/jm020180i |pmid=12502365}}</ref> 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.<ref name="LanierFeher2007">{{Cite journal |display-authors=6 |vauthors=Lanier MC, Feher M, Ashweek NJ, Loweth CJ, Rueter JK, Slee DH, Williams JP, Zhu YF, Sullivan SK, Brown MS |date=August 2007 |title=Selection, synthesis, and structure-activity relationship of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists |journal=Bioorganic & Medicinal Chemistry |volume=15 |issue=16 |pages=5590–5603 |doi=10.1016/j.bmc.2007.05.029 |pmid=17561404}}</ref><ref name="AdisInsight">{{Cite web |title=Sufugolix - Takeda |url=http://adisinsight.springer.com/drugs/800017215 |url-status=live |archive-url=https://web.archive.org/web/20160304193149/http://adisinsight.springer.com/drugs/800017215 |archive-date=2016-03-04 |access-date=2015-10-12 |website=AdisInsight |publisher=Springer Nature Switzerland AG}}</ref> 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.<ref name="pmid21657270">{{Cite journal |display-authors=6 |vauthors=Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T |date=July 2011 |title=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=Journal of Medicinal Chemistry |volume=54 |issue=14 |pages=4998–5012 |doi=10.1021/jm200216q |pmid=21657270}}</ref>

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.<ref name="pmid12502365" /> The duration of action was more than 24 hours, indicating a long elimination half-life of the drug.<ref name="pmid12502365" /> The suppressive effects of sufugolix on gonadotropin and sex hormone levels are rapidly reversible with discontinuation.<ref name="pmid12679460">{{Cite journal |display-authors=6 |vauthors=Hara T, Araki H, Kusaka M, Harada M, Cho N, Suzuki N, Furuya S, Fujino M |date=April 2003 |title=Suppression of a pituitary-ovarian axis by chronic oral administration of a novel nonpeptide gonadotropin-releasing hormone antagonist, TAK-013, in cynomolgus monkeys |journal=The Journal of Clinical Endocrinology and Metabolism |volume=88 |issue=4 |pages=1697–1704 |doi=10.1210/jc.2002-021065 |pmid=12679460 |doi-access=free}}</ref>

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.<ref name="pmid17409285">{{Cite journal |vauthors=Kohout TA, Xie Q, Reijmers S, Finn KJ, Guo Z, Zhu YF, Struthers RS |date=August 2007 |title=Trapping of a nonpeptide ligand by the extracellular domains of the gonadotropin-releasing hormone receptor results in insurmountable antagonism |journal=Molecular Pharmacology |volume=72 |issue=2 |pages=238–247 |doi=10.1124/mol.107.035535 |pmid=17409285 |s2cid=23980337}}</ref><ref name="pmid17522183">{{Cite journal |vauthors=Szkudlinski MW |date=August 2007 |title=Challenges and opportunities of trapping ligands |journal=Molecular Pharmacology |volume=72 |issue=2 |pages=231–234 |doi=10.1124/mol.107.038208 |pmid=17522183 |s2cid=25807899}}</ref>

== References == {{Reflist}}

== External links == * [http://adisinsight.springer.com/drugs/800017215 Sufugolix - AdisInsight]

Category:Abandoned drugs Category:Tertiary amines Category:Fluoroarenes Category:Gonadotropin-releasing hormone antagonists Category:Thienopyrimidines Category:Ureas