Sufugolix: Difference between revisions
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{{Short description|Chemical compound}} |
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{{Drugbox |
{{Drugbox |
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| Verifiedfields = |
| Verifiedfields = |
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| Watchedfields = |
| Watchedfields = |
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| verifiedrevid = |
| verifiedrevid = |
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| IUPAC_name = |
| 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 |
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| image = |
| image = Sufugolix.svg |
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| width = |
| width = 250px |
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<!--Clinical data--> |
<!--Clinical data--> |
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| tradename = |
| tradename = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B |
| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = |
| pregnancy_category = |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_US = |
| legal_US = |
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| legal_status = |
| legal_status = |
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| routes_of_administration = [[ |
| routes_of_administration = [[Oral administration|By mouth]] |
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| class = [[GnRH modulator]]; [[GnRH antagonist]]; [[Antigonadotropin]] |
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<!--Pharmacokinetic data--> |
<!--Pharmacokinetic data--> |
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| metabolism = |
| metabolism = |
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| elimination_half-life = |
| elimination_half-life = |
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| excretion = |
| excretion = |
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<!--Identifiers--> |
<!--Identifiers--> |
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| CAS_number = 308831-61-0 |
| CAS_number = 308831-61-0 |
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| CAS_supplemental = |
| CAS_supplemental = |
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| ATC_prefix = |
| ATC_prefix = None |
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| ATC_suffix = |
| ATC_suffix = |
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| PubChem = 3038517 |
| PubChem = 3038517 |
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| DrugBank_Ref = |
| DrugBank_Ref = |
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| ChemSpiderID_Ref = |
| ChemSpiderID_Ref = |
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| ChemSpiderID = 2302081 |
| ChemSpiderID = 2302081 |
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| UNII = 56S17Z6X9M |
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<!--Chemical data--> |
<!--Chemical data--> |
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| C=36 | H=31 | F=2 | N=5 | O=4 | S=1 |
| C=36 | H=31 | F=2 | N=5 | O=4 | S=1 |
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| SMILES = CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1 |
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| molecular_weight = 667.724246 g/mol |
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| 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 |
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| StdInChI_Ref = |
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| StdInChI = |
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| StdInChIKey_Ref = |
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| StdInChIKey = |
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}} |
}} |
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'''Sufugolix''' ( |
'''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 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> |
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Oral administration of sufugolix at a dose of 30 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 [[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 = |
Oral administration of sufugolix at a dose of 30 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> |
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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 = |
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> |
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==See also== |
== See also == |
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* [[Gonadotropin-releasing hormone receptor#Antagonists|Gonadotropin-releasing hormone receptor § Antagonists]] |
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* [[Relugolix]] |
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* [[Elagolix]] |
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==References== |
== References == |
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{{Reflist |
{{Reflist}} |
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==External links== |
== External links == |
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* [http://adisinsight.springer.com/drugs/800017215 Sufugolix - AdisInsight] |
* [http://adisinsight.springer.com/drugs/800017215 Sufugolix - AdisInsight] |
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{{Gonadotropins and GnRH}} |
{{Gonadotropins and GnRH}} |
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{{GnRH and gonadotropin receptor modulators}} |
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{{Peptidergics}} |
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[[Category:Amines]] |
[[Category:Amines]] |
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[[Category:Fluoroarenes]] |
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[[Category:GnRH antagonists]] |
[[Category:GnRH antagonists]] |
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[[Category:Pyrimidines]] |
[[Category:Pyrimidines]] |
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[[Category:Ureas]] |
[[Category:Ureas]] |
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{{ |
{{Systemic-hormonal-drug-stub}} |
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Latest revision as of 21:09, 27 May 2024
Clinical data | |
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Other names | TAK-013 |
Routes of administration | By mouth |
Drug class | GnRH modulator; GnRH antagonist; Antigonadotropin |
ATC code |
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Identifiers | |
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CAS Number | |
PubChem CID | |
ChemSpider | |
UNII | |
CompTox Dashboard (EPA) | |
Chemical and physical data | |
Formula | C36H31F2N5O4S |
Molar mass | 667.73 g·mol−1 |
3D model (JSmol) | |
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Sufugolix (INN , BAN ) (developmental code name TAK-013) is a non-peptide, orally-active, selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (IC50 = 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]- ^ 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.