Semaxanib

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

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.{{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}}{{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}}

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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.{{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 }}{{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 }}{{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 }}

• Toceranib

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{{Extracellular chemotherapeutic agents}}

{{Growth factor receptor modulators}}

Category:Receptor tyrosine kinase inhibitors

Category:Experimental cancer drugs

Category:Indolines

Category:Lactams

Category:Pyrroles

Category:Oxindoles

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