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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields =
| Verifiedfields =
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| verifiedrevid =
| 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
| 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_structure.png
| image = Sufugolix.svg
| width = 250px
| width = 250px


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<!--Chemical data-->
<!--Chemical data-->
| C=36 | H=31 | F=2 | N=5 | O=4 | S=1
| 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
| molecular_weight = 667.724 g/mol
| SMILES = CN(CC1=CC=CC=C1)CC2=C(SC3=C2C(=O)N(C(=O)N3CC4=C(C=CC=C4F)F)C5=CC=CC=C5)C6=CC=C(C=C6)NC(=O)NOC
| 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)
| 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
| StdInChIKey = UCQSBGOFELXYIN-UHFFFAOYSA-N
}}
}}


'''Sufugolix''' ({{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}) (developmental code name '''TAK-013''') is a [[non-peptide]], [[Bioavailability#In pharmacology|orally]]-active, [[binding selectivity|selective]] [[gonadotropin-releasing hormone receptor antagonist|antagonist]] of the [[gonadotropin-releasing hormone receptor]] (GnRHR) ({{abbrlink|IC<sub>50</sub>|Half-maximal inhibitory concentration}} = 0.1 and 0.06&nbsp;nM for [[affinity (pharmacology)|affinity]] and ''in vitro'' [[receptor antagonist|inhibition]], respectively).<ref name="pmid12502365">{{cite journal | vauthors = Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M | 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 = J. Med. Chem. | volume = 46 | issue = 1 | pages = 113–24 | year = 2003 | pmid = 12502365 | doi = 10.1021/jm020180i | url = }}</ref> It was under development by [[Takeda]] for the treatment of [[endometriosis]] and [[uterine leiomyoma]] and reached [[Phases of clinical research#Phase II|phase II]] [[clinical trial]]s for both of these indications, but was subsequently discontinued.<ref name="LanierFeher2007">{{cite journal|last1=Lanier|first1=Marion C.|last2=Feher|first2=Miklos|last3=Ashweek|first3=Neil J.|last4=Loweth|first4=Colin J.|last5=Rueter|first5=Jaimie K.|last6=Slee|first6=Deborah H.|last7=Williams|first7=John P.|last8=Zhu|first8=Yun-Fei|last9=Sullivan|first9=Susan K.|last10=Brown|first10=Michael S.|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|year=2007|pages=5590–5603|issn=0968-0896|doi=10.1016/j.bmc.2007.05.029|pmid=17561404}}</ref><ref name="AdisInsight">http://adisinsight.springer.com/drugs/800017215</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]] [[enzyme inhibition|inhibition]] and improved ''in vivo'' GnRHR antagonistic activity) in comparison.<ref name="pmid21657270">{{cite journal | 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 | 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 = J. Med. Chem. | volume = 54 | issue = 14 | pages = 4998–5012 | year = 2011 | pmid = 21657270 | doi = 10.1021/jm200216q | url = }}</ref>
'''Sufugolix''' ({{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}) (developmental code name '''TAK-013''') is a [[non-peptide]], [[Bioavailability#In pharmacology|orally]]-active, [[binding selectivity|selective]] [[gonadotropin-releasing hormone receptor antagonist|antagonist]] of the [[gonadotropin-releasing hormone receptor]] (GnRHR) ({{abbrlink|IC<sub>50</sub>|Half-maximal inhibitory concentration}} = 0.1 and 0.06&nbsp;nM for [[affinity (pharmacology)|affinity]] and ''in vitro'' [[receptor antagonist|inhibition]], respectively).<ref name="pmid12502365">{{cite journal | vauthors = Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M | display-authors = 6 | 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 | date = January 2003 | pmid = 12502365 | doi = 10.1021/jm020180i }}</ref> It was under development by [[Takeda Pharmaceutical Company|Takeda]] for the treatment of [[endometriosis]] and [[uterine leiomyoma]] and reached [[Phases of clinical research#Phase II|phase II]] [[clinical trial]]s for both of these indications, but was subsequently discontinued.<ref name="LanierFeher2007">{{cite journal | vauthors = Lanier MC, Feher M, Ashweek NJ, Loweth CJ, Rueter JK, Slee DH, Williams JP, Zhu YF, Sullivan SK, Brown MS | display-authors = 6 | 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 | date = August 2007 | pmid = 17561404 | doi = 10.1016/j.bmc.2007.05.029 }}</ref><ref name="AdisInsight">{{Cite web | url = http://adisinsight.springer.com/drugs/800017215 | title = Sufugolix - Takeda | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 2015-10-12 | archive-date = 2016-03-04 | archive-url = https://web.archive.org/web/20160304193149/http://adisinsight.springer.com/drugs/800017215 | url-status = live }}</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]] [[enzyme inhibition|inhibition]] and improved ''in vivo'' GnRHR antagonistic activity) in comparison.<ref name="pmid21657270">{{cite journal | 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 | display-authors = 6 | 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 | date = July 2011 | pmid = 21657270 | doi = 10.1021/jm200216q }}</ref>


Oral administration of sufugolix at a dose of 30&nbsp;mg/kg to [[castration|castrated]] male [[cynomolgus monkey]]s 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 | vauthors = Hara T, Araki H, Kusaka M, Harada M, Cho N, Suzuki N, Furuya S, Fujino M | 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 = J. Clin. Endocrinol. Metab. | volume = 88 | issue = 4 | pages = 1697–704 | year = 2003 | pmid = 12679460 | doi = 10.1210/jc.2002-021065 | url = }}</ref>
Oral administration of sufugolix at a dose of 30&nbsp;mg/kg to [[castration|castrated]] male [[cynomolgus monkey]]s 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 | vauthors = Hara T, Araki H, Kusaka M, Harada M, Cho N, Suzuki N, Furuya S, Fujino M | display-authors = 6 | 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 | date = April 2003 | pmid = 12679460 | doi = 10.1210/jc.2002-021065 | doi-access = free }}</ref>


Unlike various other GnRHR antagonists, sufugolix has been elucidated to be a [[non-competitive antagonist|non-competitive or insurmountable/trapping antagonist]] of the GnRHR.<ref name="pmid17409285">{{cite journal | vauthors = Kohout TA, Xie Q, Reijmers S, Finn KJ, Guo Z, Zhu YF, Struthers RS | title = Trapping of a nonpeptide ligand by the extracellular domains of the gonadotropin-releasing hormone receptor results in insurmountable antagonism | journal = Mol. Pharmacol. | volume = 72 | issue = 2 | pages = 238–47 | year = 2007 | pmid = 17409285 | doi = 10.1124/mol.107.035535 | url = }}</ref><ref name="pmid17522183">{{cite journal | vauthors = Szkudlinski MW | title = Challenges and opportunities of trapping ligands | journal = Mol. Pharmacol. | volume = 72 | issue = 2 | pages = 231–4 | year = 2007 | pmid = 17522183 | doi = 10.1124/mol.107.038208 | url = }}</ref>
Unlike various other GnRHR antagonists, sufugolix has been elucidated to be a [[non-competitive antagonist|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 | 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 | date = August 2007 | pmid = 17409285 | doi = 10.1124/mol.107.035535 | s2cid = 23980337 }}</ref><ref name="pmid17522183">{{cite journal | vauthors = Szkudlinski MW | title = Challenges and opportunities of trapping ligands | journal = Molecular Pharmacology | volume = 72 | issue = 2 | pages = 231–234 | date = August 2007 | pmid = 17522183 | doi = 10.1124/mol.107.038208 | s2cid = 25807899 }}</ref>


==See also==
== See also ==
* [[Gonadotropin-releasing hormone receptor#Antagonists|Gonadotropin-releasing hormone receptor § Antagonists]]
* [[Gonadotropin-releasing hormone receptor#Antagonists|Gonadotropin-releasing hormone receptor § Antagonists]]


==References==
== References ==
{{Reflist|2}}
{{Reflist}}


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



{{Gonadotropins and GnRH}}
{{Gonadotropins and GnRH}}
{{Signaling peptide/protein receptor modulators}}
{{GnRH and gonadotropin receptor modulators}}


[[Category:Abandoned drugs]]
[[Category:Abandoned drugs]]
Line 72: Line 71:
[[Category:Fluoroarenes]]
[[Category:Fluoroarenes]]
[[Category:GnRH antagonists]]
[[Category:GnRH antagonists]]
[[Category:Pyrimidines]]
[[Category:Thienopyrimidines]]
[[Category:Ureas]]
[[Category:Ureas]]



{{Genito-urinary-drug-stub}}
{{Genito-urinary-drug-stub}}

Latest revision as of 04:05, 25 September 2024

Sufugolix
Clinical data
Other namesTAK-013
Routes of
administration		By mouth
Drug classGnRH modulator; GnRH antagonist; Antigonadotropin
ATC code
  • None
Identifiers
  • 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
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC36H31F2N5O4S
Molar mass667.73 g·mol−1
3D model (JSmol)
  • CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
  • 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]

See also

[edit]

References

[edit]
  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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