Wikipedia

Sufugolix

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]

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

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

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References

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  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 12502365.113-124&rft.date=2003-01&rft_id=info:doi/10.1021/jm020180i&rft_id=info:pmid/12502365&rft.aulast=Sasaki&rft.aufirst=S&rft.au=Cho, N&rft.au=Nara, Y&rft.au=Harada, M&rft.au=Endo, S&rft.au=Suzuki, N&rft.au=Furuya, S&rft.au=Fujino, M&rfr_id=info:sid/en.wikipedia.org:Sufugolix" class="Z3988">
  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 17561404.5590-5603&rft.date=2007-08&rft_id=info:doi/10.1016/j.bmc.2007.05.029&rft_id=info:pmid/17561404&rft.aulast=Lanier&rft.aufirst=MC&rft.au=Feher, M&rft.au=Ashweek, NJ&rft.au=Loweth, CJ&rft.au=Rueter, JK&rft.au=Slee, DH&rft.au=Williams, JP&rft.au=Zhu, YF&rft.au=Sullivan, SK&rft.au=Brown, MS&rfr_id=info:sid/en.wikipedia.org:Sufugolix" class="Z3988">
  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 21657270.4998-5012&rft.date=2011-07&rft_id=info:doi/10.1021/jm200216q&rft_id=info:pmid/21657270&rft.aulast=Miwa&rft.aufirst=K&rft.au=Hitaka, T&rft.au=Imada, T&rft.au=Sasaki, S&rft.au=Yoshimatsu, M&rft.au=Kusaka, M&rft.au=Tanaka, A&rft.au=Nakata, D&rft.au=Furuya, S&rft.au=Endo, S&rft.au=Hamamura, K&rft.au=Kitazaki, T&rfr_id=info:sid/en.wikipedia.org:Sufugolix" class="Z3988">
  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 12679460.1697-1704&rft.date=2003-04&rft_id=info:doi/10.1210/jc.2002-021065&rft_id=info:pmid/12679460&rft.aulast=Hara&rft.aufirst=T&rft.au=Araki, H&rft.au=Kusaka, M&rft.au=Harada, M&rft.au=Cho, N&rft.au=Suzuki, N&rft.au=Furuya, S&rft.au=Fujino, M&rft_id=https://doi.org/10.1210%2Fjc.2002-021065&rfr_id=info:sid/en.wikipedia.org:Sufugolix" class="Z3988">
  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 23980337.238-247&rft.date=2007-08&rft_id=https://api.semanticscholar.org/CorpusID:23980337#id-name=S2CID&rft_id=info:pmid/17409285&rft_id=info:doi/10.1124/mol.107.035535&rft.aulast=Kohout&rft.aufirst=TA&rft.au=Xie, Q&rft.au=Reijmers, S&rft.au=Finn, KJ&rft.au=Guo, Z&rft.au=Zhu, YF&rft.au=Struthers, RS&rfr_id=info:sid/en.wikipedia.org:Sufugolix" class="Z3988">
  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 25807899.231-234&rft.date=2007-08&rft_id=https://api.semanticscholar.org/CorpusID:25807899#id-name=S2CID&rft_id=info:pmid/17522183&rft_id=info:doi/10.1124/mol.107.038208&rft.aulast=Szkudlinski&rft.aufirst=MW&rfr_id=info:sid/en.wikipedia.org:Sufugolix" class="Z3988">
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