Discovery of 5-[[4-[(2,3-Dimethyl-2 H -indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor †

✍ Scribed by Harris, Philip A.; Boloor, Amogh; Cheung, Mui; Kumar, Rakesh; Crosby, Renae M.; Davis-Ward, Ronda G.; Epperly, Andrea H.; Hinkle, Kevin W.; Hunter, Robert N.; Johnson, Jennifer H.; Knick, Victoria B.; Laudeman, Christopher P.; Luttrell, Deirdre K.; Mook, Robert A.; Nolte, Robert T.; Rudolph, Sharon K.; Szewczyk, Jerzy R.; Truesdale, Anne T.; Veal, James M.; Wang, Liping; Stafford, Jeffrey A.

• Book ID: 118162923
• Publisher: American Chemical Society
• Year: 2008
• Tongue: English
• Weight: 591 KB
• Volume: 51
• Category: Article
• ISSN: 0022-2623
• DOI: 10.1021/jm800566m

✦ Synopsis

Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N 4 -(2,3-dimethyl-2H-indazol-6-yl)-N 4 -methyl-N 2 -(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors. † Coordinates for the VEGFR2 complexes with compounds 5a and 11b have been deposited into the Protein Data Bank under accession codes 3CJF and 3CJG, respectively.