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{{Short description|Chemical compound}}
{{Distinguish|Semax}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 464389051
| IUPAC_name = (3''Z'')-3-[(3,5-dimethyl-1''H''-pyrrol-2-yl)methylidene]-1,3-dihydro-2''H''-indol-2-one
| IUPAC_name = (3''Z'')-3-[(3,5-dimethyl-1''H''-pyrrol-2-yl)methylidene]-1,3-dihydro-2''H''-indol-2-one
| image = Semaxanib.svg
| image = Semaxanib.svg


<!--Clinical data-->
<!--Clinical data-->
| tradename =
| tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status =
| legal_status =
| routes_of_administration =
| routes_of_administration =


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability =
| bioavailability =
| protein_bound =
| protein_bound =
| metabolism =
| metabolism =
| elimination_half-life =
| elimination_half-life =
| excretion =
| excretion =


<!--Identifiers-->
<!--Identifiers-->
| IUPHAR_ligand = 5056
| IUPHAR_ligand = 5056
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 194413-58-6
| CAS_number = 194413-58-6
| ATC_prefix = none
| ATC_prefix = none
| ATC_suffix =
| ATC_suffix =
| PubChem = 5329098
| PubChem = 5329098
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4486260
| ChemSpiderID = 4486260
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 91083
| ChEBI = 91083
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}}
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<!--Chemical data-->
<!--Chemical data-->
| C=15 | H=14 | N=2 | O=1
| C=15 | H=14 | N=2 | O=1
⚫
| smiles = O=C2C(\c1ccccc1N2)=C/c3c(cc([nH]3)C)C
| molecular_weight = 238.285 g/mol
⚫
| smiles = O=C2C(\c1ccccc1N2)=C/c3c(cc(n3)C)C
| InChI = 1/C15H14N2O/c1-9-7-10(2)16-14(9)8-12-11-5-3-4-6-13(11)17-15(12)18/h3-8,16H,1-2H3,(H,17,18)/b12-8-
| InChIKey = WUWDLXZGHZSWQZ-WQLSENKSBZ
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C15H14N2O/c1-9-7-10(2)16-14(9)8-12-11-5-3-4-6-13(11)17-15(12)18/h3-8,16H,1-2H3,(H,17,18)/b12-8-
| StdInChI = 1S/C15H14N2O/c1-9-7-10(2)16-14(9)8-12-11-5-3-4-6-13(11)17-15(12)18/h3-8,16H,1-2H3,(H,17,18)/b12-8-
Line 53: Line 51:
| StdInChIKey = WUWDLXZGHZSWQZ-WQLSENKSSA-N
| StdInChIKey = WUWDLXZGHZSWQZ-WQLSENKSSA-N
}}
}}
'''Semaxanib'''<ref>{{cite journal | author = [[World Health Organization]] | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 85 | journal = WHO Drug Information | volume = 15 | issue = 2 | year = 2001}} {{PDFlink|[http://www.who.int/druginformation/vol15num2_2001/list_85.pdf Full text]|244&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 250247 bytes -->}}</ref> ('''SU5416''') is a [[tyrosine-kinase inhibitor]] drug designed by [[SUGEN]] as a cancer therapeutic. It is an [[investigational product|experimental stage]] drug, not [[Regulation of therapeutic goods|licensed]] for use on human patients outside of [[clinical trial]]s.
'''Semaxanib''' ([[International Nonproprietary Name|INN]],<ref>{{cite journal | author = World Health Organization | author-link = World Health Organization | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 85 | journal = WHO Drug Information | volume = 15 | issue = 2 | year = 2001}} {{cite web |url=https://www.who.int/druginformation/vol15num2_2001/list_85.pdf |title= Full text |url-status= dead |archive-url= https://web.archive.org/web/20070316041248/http://www.who.int/druginformation/vol15num2_2001/list_85.pdf |archive-date= 2007-03-16 }}&nbsp;{{small|(244&nbsp;[[Kibibyte|KiB]])}}</ref> codenamed '''SU5416''') is a [[tyrosine-kinase inhibitor]] drug designed by [[SUGEN]] as a cancer therapeutic. It is an [[investigational new drug|experimental stage drug]], not [[Regulation of therapeutic goods|licensed]] for use on human patients outside [[clinical trial]]s.
Semaxanib is a potent and selective synthetic [[kinase inhibitor|inhibitor]] of the Flk-1/KDR [[vascular endothelial growth factor]] (VEGF) receptor [[tyrosine kinase]]. It targets the [[VEGF pathway]], and both ''[[in vivo]]'' and ''[[in vitro]]'' studies have demonstrated [[antiangiogenic]] potential.
Semaxanib is a potent and selective synthetic [[kinase inhibitor|inhibitor]] of the Flk-1/KDR [[vascular endothelial growth factor]] (VEGF) receptor [[tyrosine kinase]]. It targets the [[VEGF pathway]], and both ''[[in vivo]]'' and ''[[in vitro]]'' studies have demonstrated [[antiangiogenic]] potential.{{cn|date=February 2023}}


==Research==
On February 2002, [[Pharmacia]], the then-parent of Sugen, prematurely ended [[Clinical trial#Phase III|Phase III]] clinical trials of semaxinib in the treatment of advanced [[colorectal cancer]] due to discouraging results.<ref>{{cite press release | url = http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/02-08-2002/0001665238&EDATE= | title =
⚫
Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials | date = February 8, 2002 | accessdate = 2007-03-20}}</ref> Other studies, at earlier phases, have since been conducted.<ref>{{cite journal |author=O'Donnell A, Padhani A, Hayes C, Kakkar A, Leach M, Trigo J, Scurr M, Raynaud F, Phillips S, Aherne W, Hardcastle A, Workman P, Hannah A, Judson I |title=A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points |journal=Br J Cancer |volume=93 |issue=8 |pages=876–83 |year=2005 |pmid=16222321 |doi=10.1038/sj.bjc.6602797 |pmc=2361651}}</ref><ref>{{cite journal |author=Lockhart A, Cropp G, Berlin J, Donnelly E, Schumaker R, Schaaf L, Hande K, Fleischer A, Hannah A, Rothenberg M |title=Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer |journal=Am J Clin Oncol |volume=29 |issue=2 |pages=109–15 |year=2006 |pmid=16601426 |doi=10.1097/01.coc.0000199882.53545.ac}}</ref> However, due to the prospect of next-generation tyrosine kinase inhibitors and the ineffaciousness of semaxanib in clinic trials, further development of the drug has been discontinued.<ref>{{cite journal|url=http://jjco.oxfordjournals.org/cgi/content/full/36/2/100 |author= Hoff, PM|title=A Phase I Study of Escalating Doses of the Tyrosine Kinase Inhibitor Semaxanib (SU5416) in Combination with Irinotecan in Patients with Advanced Colorectal Carcinoma |journal=Japanese Journal of Clinical Oncology |volume=36 |issue=2 |pages=100–103|year=2006 |doi=10.1093/jjco/hyi229|pmid=16449240|display-authors=etal}}</ref> A related compound, SU11248 was further developed by Sugen, and then by [[Pfizer]] and was FDA-approved as [[sunitinib]] (Sutent) for treatment of renal carcinoma in January 2006.


⚫
In February 2002, [[Pharmacia]], the then-parent of Sugen, prematurely ended [[Clinical trial#Phase III|phase III]] clinical trials of semaxinib in the treatment of advanced [[colorectal cancer]] due to discouraging results.<ref>{{cite press release | url = http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/02-08-2002/0001665238&EDATE= | title = Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials | date = February 8, 2002 | access-date = 2007-03-20}}</ref> Other studies, at earlier phases, have since been conducted.<ref>{{cite journal | vauthors = O'Donnell A, Padhani A, Hayes C, Kakkar AJ, Leach M, Trigo JM, Scurr M, Raynaud F, Phillips S, Aherne W, Hardcastle A, Workman P, Hannah A, Judson I | title = A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points | journal = British Journal of Cancer | volume = 93 | issue = 8 | pages = 876–83 | date = October 2005 | pmid = 16222321 | pmc = 2361651 | doi = 10.1038/sj.bjc.6602797 }}</ref><ref>{{cite journal | vauthors = Lockhart AC, Cropp GF, Berlin JD, Donnelly E, Schumaker RD, Schaaf LJ, Hande KR, Fleischer AC, Hannah AL, Rothenberg ML | title = Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer | journal = American Journal of Clinical Oncology | volume = 29 | issue = 2 | pages = 109–15 | date = April 2006 | pmid = 16601426 | doi = 10.1097/01.coc.0000199882.53545.ac | s2cid = 26566099 }}</ref> However, due to the prospect of next-generation tyrosine kinase inhibitors and the inefficacy of semaxanib in clinic trials, further development of the drug has been discontinued.<ref>{{cite journal | vauthors = Hoff PM, Wolff RA, Bogaard K, Waldrum S, Abbruzzese JL | title = A Phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma | journal = Japanese Journal of Clinical Oncology | volume = 36 | issue = 2 | pages = 100–3 | date = February 2006 | pmid = 16449240 | doi = 10.1093/jjco/hyi229 | doi-access = free }}</ref> A related compound, SU11248 ([[sunitinib]]), was further developed by Sugen and subsequently by [[Pfizer]], and received FDA approval for treatment of renal carcinoma in January 2006.<ref name="FDA">{{cite web | publisher = U.S. [[Food and Drug Administration]] (FDA) | title = FDA approves new treatment for gastrointestinal and kidney cancer | url=https://www.fda.gov/bbs/topics/news/2006/NEW01302.html | archive-url=https://web.archive.org/web/20060203031129/http://www.fda.gov/bbs/topics/news/2006/NEW01302.html | url-status=dead | archive-date=3 February 2006 |year=2006 }}</ref>
⚫
==References==

When combined with chronic exposure to [[Hypoxia (medical)|hypoxia]], SU5416 induces severe [[pulmonary hypertension]] in [[laboratory mouse|mice]] and [[laboratory rat|rat]]s. This property has been exploited to develop a series of useful, though controversial, [[animal testing on rodents|rodent models]] of pulmonary arterial hypertension, the first and best characterized being the Sugen/Hypoxia (SuHx) mouse model.<ref>{{cite journal |vauthors=Vitali SH, Hansmann G, Rose C, Fernandez-Gonzalez A, Scheid A, Mitsialis SA, Kourembanas S |title=The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up |journal=Pulm Circ |volume=4 |issue=4 |pages=619–29 |date=December 2014 |pmid=25610598 |pmc=4278622 |doi=10.1086/678508}}</ref><ref>{{cite journal |vauthors=Voelkel NF, Bogaard HJ |title=Sugen, hypoxia and the lung circulation |journal=Pulm Circ |volume=11 |issue=4 |pages=20458940211051188 |date=2021 |pmid=34631012 |pmc=8493318 |doi=10.1177/20458940211051188}}</ref>

==Synthesis==
:[[File:Semaxanib synthesis.svg|upright=2]]
A [[Vilsmeier–Haack reaction]] on 2,4-dimethylpyrrole (1) gives the [[aldehyde]] (2). [[Knoevenagel condensation]] of this intermediate with [[oxindole]] (3) in the presence of base yields semaxanib.<ref>{{cite journal | vauthors = Sun L, Tran N, Tang F, App H, Hirth P, McMahon G, Tang C | title = Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases | journal = Journal of Medicinal Chemistry | volume = 41 | issue = 14 | pages = 2588–2603 | date = July 1998 | pmid = 9651163 | doi = 10.1021/jm980123i }}</ref><ref>{{cite journal |doi=10.1016/j.tet.2010.03.018 |title=Tandem Horner–Wadsworth–Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: The synthesis of Semaxanib and GW441756 |date=2010 | vauthors = Lubkoll J, Millemaggi A, Perry A, Taylor RJ|journal=Tetrahedron |volume=66 |issue=33 |pages=6606–6612 }}</ref><ref>{{cite journal |doi=10.1016/j.tet.2009.04.014 |title=Synthesis of potential prodrug systems for reductive activation. Prodrugs for anti-angiogenic isoflavones and VEGF receptor tyrosine kinase inhibitory oxindoles |date=2009 | vauthors = Blanche EA, Maskell L, Colucci MA, Whatmore JL, Moody CJ |journal=Tetrahedron |volume=65 |issue=25 |pages=4894–4903 }}</ref>

==See also==
*[[Toceranib]]

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


{{Extracellular chemotherapeutic agents}}
{{Extracellular chemotherapeutic agents}}
{{Growth factor receptor modulators}}


[[Category:Receptor tyrosine kinase inhibitors]]
[[Category:Receptor tyrosine kinase inhibitors]]
[[Category:Experimental cancer drugs]]
[[Category:Indolines]]
[[Category:Indolines]]
[[Category:Lactams]]
[[Category:Lactams]]
[[Category:Pyrroles]]
[[Category:Pyrroles]]
[[Category:Oxindoles]]




Latest revision as of 14:13, 18 July 2024

Not to be confused with Semax.

Semaxanib
Clinical data
ATC code
  • none
Identifiers
  • (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC15H14N2O
Molar mass238.290 g·mol−1
3D model (JSmol)
  • O=C2C(\c1ccccc1N2)=C/c3c(cc([nH]3)C)C
  • InChI=1S/C15H14N2O/c1-9-7-10(2)16-14(9)8-12-11-5-3-4-6-13(11)17-15(12)18/h3-8,16H,1-2H3,(H,17,18)/b12-8- checkY
  • Key:WUWDLXZGHZSWQZ-WQLSENKSSA-N checkY

Semaxanib (INN,[1] codenamed SU5416) is a tyrosine-kinase inhibitor drug designed by SUGEN as a cancer therapeutic. It is an experimental stage drug, not licensed for use on human patients outside clinical trials. Semaxanib is a potent and selective synthetic inhibitor of the Flk-1/KDR vascular endothelial growth factor (VEGF) receptor tyrosine kinase. It targets the VEGF pathway, and both in vivo and in vitro studies have demonstrated antiangiogenic potential.[citation needed]

Research

[edit]

In February 2002, Pharmacia, the then-parent of Sugen, prematurely ended phase III clinical trials of semaxinib in the treatment of advanced colorectal cancer due to discouraging results.[2] Other studies, at earlier phases, have since been conducted.[3][4] However, due to the prospect of next-generation tyrosine kinase inhibitors and the inefficacy of semaxanib in clinic trials, further development of the drug has been discontinued.[5] A related compound, SU11248 (sunitinib), was further developed by Sugen and subsequently by Pfizer, and received FDA approval for treatment of renal carcinoma in January 2006.[6]

When combined with chronic exposure to hypoxia, SU5416 induces severe pulmonary hypertension in mice and rats. This property has been exploited to develop a series of useful, though controversial, rodent models of pulmonary arterial hypertension, the first and best characterized being the Sugen/Hypoxia (SuHx) mouse model.[7][8]

Synthesis

[edit]

A Vilsmeier–Haack reaction on 2,4-dimethylpyrrole (1) gives the aldehyde (2). Knoevenagel condensation of this intermediate with oxindole (3) in the presence of base yields semaxanib.[9][10][11]

See also

[edit]

References

[edit]
  1. ^ World Health Organization (2001). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 85". WHO Drug Information. 15 (2). "Full text" (PDF). Archived from the original (PDF) on 2007-03-16. (244 KiB)
  2. ^ "Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials" (Press release). February 8, 2002. Retrieved 2007-03-20.
  3. ^ O'Donnell A, Padhani A, Hayes C, Kakkar AJ, Leach M, Trigo JM, et al. (October 2005). "A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points". British Journal of Cancer. 93 (8): 876–83. doi:10.1038/sj.bjc.6602797. PMC 2361651. PMID 16222321.
  4. ^ Lockhart AC, Cropp GF, Berlin JD, Donnelly E, Schumaker RD, Schaaf LJ, et al. (April 2006). "Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer". American Journal of Clinical Oncology. 29 (2): 109–15. doi:10.1097/01.coc.0000199882.53545.ac. PMID 16601426. S2CID 26566099.
  5. ^ Hoff PM, Wolff RA, Bogaard K, Waldrum S, Abbruzzese JL (February 2006). "A Phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma". Japanese Journal of Clinical Oncology. 36 (2): 100–3. doi:10.1093/jjco/hyi229. PMID 16449240.
  6. ^ "FDA approves new treatment for gastrointestinal and kidney cancer". U.S. Food and Drug Administration (FDA). 2006. Archived from the original on 3 February 2006.
  7. ^ Vitali SH, Hansmann G, Rose C, Fernandez-Gonzalez A, Scheid A, Mitsialis SA, et al. (December 2014). "The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up". Pulm Circ. 4 (4): 619–29. doi:10.1086/678508. PMC 4278622. PMID 25610598.
  8. ^ Voelkel NF, Bogaard HJ (2021). "Sugen, hypoxia and the lung circulation". Pulm Circ. 11 (4): 20458940211051188. doi:10.1177/20458940211051188. PMC 8493318. PMID 34631012.
  9. ^ Sun L, Tran N, Tang F, App H, Hirth P, McMahon G, et al. (July 1998). "Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases". Journal of Medicinal Chemistry. 41 (14): 2588–2603. doi:10.1021/jm980123i. PMID 9651163.
  10. ^ Lubkoll J, Millemaggi A, Perry A, Taylor RJ (2010). "Tandem Horner–Wadsworth–Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: The synthesis of Semaxanib and GW441756". Tetrahedron. 66 (33): 6606–6612. doi:10.1016/j.tet.2010.03.018.
  11. ^ Blanche EA, Maskell L, Colucci MA, Whatmore JL, Moody CJ (2009). "Synthesis of potential prodrug systems for reductive activation. Prodrugs for anti-angiogenic isoflavones and VEGF receptor tyrosine kinase inhibitory oxindoles". Tetrahedron. 65 (25): 4894–4903. doi:10.1016/j.tet.2009.04.014.


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