Semaxanib Explained

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.

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]

See also

Notes and References

  1. World Health Organization . World Health Organization . International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 85 . WHO Drug Information . 15 . 2 . 2001. Web site: Full text . dead . https://web.archive.org/web/20070316041248/http://www.who.int/druginformation/vol15num2_2001/list_85.pdf . 2007-03-16 .  
  2. Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials . February 8, 2002 . 2007-03-20.
  3. 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 . 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 . 16222321 . 2361651 . 10.1038/sj.bjc.6602797 .
  4. Lockhart AC, Cropp GF, Berlin JD, Donnelly E, Schumaker RD, Schaaf LJ, Hande KR, Fleischer AC, Hannah AL, Rothenberg ML . 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 . 16601426 . 10.1097/01.coc.0000199882.53545.ac . 26566099 .
  5. Hoff PM, Wolff RA, Bogaard K, Waldrum S, Abbruzzese JL . 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 . 16449240 . 10.1093/jjco/hyi229 . free .
  6. Web site: U.S. Food and Drug Administration (FDA) . FDA approves new treatment for gastrointestinal and kidney cancer . https://web.archive.org/web/20060203031129/http://www.fda.gov/bbs/topics/news/2006/NEW01302.html . dead . 3 February 2006 . 2006 .
  7. Vitali SH, Hansmann G, Rose C, Fernandez-Gonzalez A, Scheid A, Mitsialis SA, Kourembanas S . The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up . Pulm Circ . 4 . 4 . 619–29 . December 2014 . 25610598 . 4278622 . 10.1086/678508.
  8. Voelkel NF, Bogaard HJ . Sugen, hypoxia and the lung circulation . Pulm Circ . 11 . 4 . 20458940211051188 . 2021 . 34631012 . 8493318 . 10.1177/20458940211051188.
  9. Sun L, Tran N, Tang F, App H, Hirth P, McMahon G, Tang C . 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 . 9651163 . 10.1021/jm980123i .
  10. 10.1016/j.tet.2010.03.018 . Tandem Horner–Wadsworth–Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: The synthesis of Semaxanib and GW441756 . 2010 . Lubkoll J, Millemaggi A, Perry A, Taylor RJ. Tetrahedron . 66 . 33 . 6606–6612 .
  11. 10.1016/j.tet.2009.04.014 . Synthesis of potential prodrug systems for reductive activation. Prodrugs for anti-angiogenic isoflavones and VEGF receptor tyrosine kinase inhibitory oxindoles . 2009 . Blanche EA, Maskell L, Colucci MA, Whatmore JL, Moody CJ . Tetrahedron . 65 . 25 . 4894–4903 .

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