Semaxanib

Semaxanib
Clinical data
ATC code	none;
Identifiers
	IUPAC name (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one;
CAS Number	194413-58-6 ;
PubChem CID	5329098;
IUPHAR/BPS	5056;
ChemSpider	4486260 ;
UNII	71IA9S35AJ;
ChEBI	CHEBI:91083 ;
ChEMBL	ChEMBL276711 ;
CompTox Dashboard (EPA)	DTXSID801025708 ;
Chemical and physical data
Formula	C15H14N2O
Molar mass	238.290 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C2C(\c1ccccc1N2)=C/c3c(cc([nH]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,^[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

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

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]

References

^ 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)
^ "Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials" (Press release). February 8, 2002. Retrieved 2007-03-20.
^ 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.
^ 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.
^ 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.
^ "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.
^ 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.
^ Voelkel NF, Bogaard HJ (2021). "Sugen, hypoxia and the lung circulation". Pulm Circ. 11 (4): 20458940211051188. doi:10.1177/20458940211051188. PMC 8493318. PMID 34631012.
^ 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.
^ 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.
^ 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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[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.

[FDA-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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Semaxanib

Research

Synthesis

See also

References

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