Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor.
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.
Harris
Philip A
PA
GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. philip.a.harris@gsk.com
Boloor
Amogh
A
Cheung
Mui
M
Kumar
Rakesh
R
Crosby
Renae M
RM
Davis-Ward
Ronda G
RG
Epperly
Andrea H
AH
Hinkle
Kevin W
KW
Hunter
Robert N
RN
Johnson
Jennifer H
JH
Knick
Victoria B
VB
Laudeman
Christopher P
CP
Luttrell
Deirdre K
DK
Mook
Robert A
RA
Nolte
Robert T
RT
Rudolph
Sharon K
SK
Szewczyk
Jerzy R
JR
Truesdale
Anne T
AT
Veal
James M
JM
Wang
Liping
L
Stafford
Jeffrey A
JA
D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007191:Indazoles; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D065607:Cytochrome P-450 Enzyme Inhibitors; D007191:Indazoles; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D003577:Cytochrome P-450 Enzyme System; D040262:Receptors, Vascular Endothelial Growth Factor