title: Discovery of an Orally Efficacious Imidazo[5,1-f][1,2,4]triazine Dual Inhibitor of IGF-1R and IR.
abstract: This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacological activity of compound 9b, a potent, selective, well-tolerated, and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in tumor xenograft models, is discussed.
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Meizhong
authors.initials: M
authors.lastname: Jin
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, Colorado 80301.
authors.forename: Prafulla C
authors.initials: PC
authors.lastname: Gokhale
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, Colorado 80301.
authors.forename: Andy
authors.initials: A
authors.lastname: Cooke
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Foreman
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Buck
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Earl W
authors.initials: EW
authors.lastname: May
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, Colorado 80301.
authors.forename: Lixin
authors.initials: L
authors.lastname: Feng
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, Colorado 80301.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bittner
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Mridula
authors.initials: M
authors.lastname: Kadalbajoo
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, Colorado 80301.
authors.forename: Darla
authors.initials: D
authors.lastname: Landfair
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Kam W
authors.initials: KW
authors.lastname: Siu
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Stolz
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Werner
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Radoslaw S
authors.initials: RS
authors.lastname: Laufer
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: An-Hu
authors.initials: AH
authors.lastname: Li
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Hanqing
authors.initials: H
authors.lastname: Dong
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Arno G
authors.initials: AG
authors.lastname: Steinig
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kleinberg
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Pachter
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, Colorado 80301.
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, New York 11735.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulvihill
keywords: Insulin-like growth factor-1 receptor (IGF-1R); cancer; inhibitors, structure-based drug design (SBDD); insulin receptor (IR)