Semaxanib
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Formula | C15H14N2O |
Molar mass | 238.290 g·mol−1 |
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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]
The Vilsmeier–Haack reaction on 2,4-dimethylpyrrole [625-82-1] (1) affords 3,5-dimethylpyrrole-2-carboxaldehyde [2199-58-8] (2). Knoevenagel condensation of this intermediate with oxindole [59-48-3] (3) in the presence of base affords semaxanib (4).
See also[edit]
References[edit]
- ^ 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, Scurr M, Raynaud F, Phillips S, Aherne W, Hardcastle A, Workman P, Hannah A, Judson I (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, Hande KR, Fleischer AC, Hannah AL, Rothenberg ML (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, Kourembanas S (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, Li; Tran, Ngoc; Tang, Flora; App, Harald; Hirth, Peter; McMahon, Gerald; Tang, Cho (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.
- ^ Lubkoll, Jana; Millemaggi, Alessia; Perry, Alexis; Taylor, Richard J.K. (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, Emilie A.; Maskell, Lesley; Colucci, Marie A.; Whatmore, Jacqueline L.; Moody, Christopher J. (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.
- ^ Peng Cho Tang, et al. US6846839 (2005 to Sugen Inc).