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Semaxanib

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(Redirected from SU5416) Chemical compound Not to be confused with Semax.

Pharmaceutical compound
Semaxanib
Clinical data
ATC code
  • none
Identifiers
IUPAC name
  • (3Z)-3--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
3D model (JSmol)
SMILES
  • O=C2C(\c1ccccc1N2)=C/c3c(cc(3)C)C
InChI
  • 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-
  • Key:WUWDLXZGHZSWQZ-WQLSENKSSA-N

Semaxanib (INN, 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.

Research

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. Other studies, at earlier phases, have since been conducted. 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. 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.

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.

Synthesis

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.

See also

References

  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.
Targeted cancer therapy / antineoplastic agents (L01)
CI monoclonal antibodies ("-mab")
Receptor tyrosine kinase
Others for solid tumors
Leukemia/lymphoma
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Tyrosine kinase inhibitors ("-nib")
Receptor tyrosine kinase
Non-receptor
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Growth factor receptor modulators
Angiopoietin
CNTF
EGF (ErbB)
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  • Agonists: Unknown/none
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  • Negative allosteric modulators: VM-902A
TrkB
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VEGF
Others
  • Additional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)


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