Chemistry:Semaxanib
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
- 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.[9][10][11]
See also
References
- ↑ World Health Organization (2001). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 85". WHO Drug Information 15 (2). "Full text". https://www.who.int/druginformation/vol15num2_2001/list_85.pdf. (244 KiB)
- ↑ "Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials" (Press release). February 8, 2002. Retrieved 2007-03-20.
- ↑ "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. October 2005. doi:10.1038/sj.bjc.6602797. PMID 16222321.
- ↑ "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. April 2006. doi:10.1097/01.coc.0000199882.53545.ac. PMID 16601426.
- ↑ "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. February 2006. doi:10.1093/jjco/hyi229. PMID 16449240.
- ↑ "FDA approves new treatment for gastrointestinal and kidney cancer". U.S. Food and Drug Administration (FDA). 2006. https://www.fda.gov/bbs/topics/news/2006/NEW01302.html.
- ↑ "The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up". Pulm Circ 4 (4): 619–29. December 2014. doi:10.1086/678508. PMID 25610598.
- ↑ "Sugen, hypoxia and the lung circulation". Pulm Circ 11 (4). 2021. doi:10.1177/20458940211051188. PMID 34631012.
- ↑ "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. July 1998. doi:10.1021/jm980123i. PMID 9651163.
- ↑ "Tandem Horner–Wadsworth–Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: The synthesis of Semaxanib and GW441756". Tetrahedron 66 (33): 6606–6612. 2010. doi:10.1016/j.tet.2010.03.018.
- ↑ "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. 2009. doi:10.1016/j.tet.2009.04.014.
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