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'''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 }}</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> |
'''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 [[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> |
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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Latest revision as of 21:09, 27 May 2024
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| 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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| 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.
External links[edit]
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