title: 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.
abstract: 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.
authors.affiliation: GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. philip.a.harris@gsk.com
authors.forename: Philip A
authors.initials: PA
authors.lastname: Harris
authors.forename: Amogh
authors.initials: A
authors.lastname: Boloor
authors.forename: Mui
authors.initials: M
authors.lastname: Cheung
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Renae M
authors.initials: RM
authors.lastname: Crosby
authors.forename: Ronda G
authors.initials: RG
authors.lastname: Davis-Ward
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Epperly
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hinkle
authors.forename: Robert N
authors.initials: RN
authors.lastname: Hunter
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Johnson
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Knick
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Laudeman
authors.forename: Deirdre K
authors.initials: DK
authors.lastname: Luttrell
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mook
authors.forename: Robert T
authors.initials: RT
authors.lastname: Nolte
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Rudolph
authors.forename: Jerzy R
authors.initials: JR
authors.lastname: Szewczyk
authors.forename: Anne T
authors.initials: AT
authors.lastname: Truesdale
authors.forename: James M
authors.initials: JM
authors.lastname: Veal
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Stafford
mesh_terms: 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
chemical_list: 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