Semaxanib

Not to be confused with Semax.

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]}

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 Y
PubChem CID	5329098
IUPHAR/BPS	5056
ChemSpider	4486260 Y
UNII	71IA9S35AJ
ChEBI	CHEBI:91083 Y
ChEMBL	ChEMBL276711 Y
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- Y Key:WUWDLXZGHZSWQZ-WQLSENKSSA-N Y

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

• Toceranib