- Discovery of a 2,4-disubstituted pyrrolo-[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development
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This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development. 2009 American Chemical Society.
- Wittman, Mark D.,Carboni, Joan M.,Yang, Zheng,Lee, Francis Y.,Antman, Melissa,Attar, Ricardo,Balimane, Praveen,Chang, Chiehying,Chen, Cliff,Discenza, Lorell,Frennesson, David,Gottardis, Marco M.,Greer, Ann,Hurlburt, Warren,Johnson, Walter,Langley, David R.,Li, Aixin,Li, Jianqing,Liu, Peiying,Mastalerz, Harold,Mathur, Arvind,Menard, Krista,Patel, Karishma,Sack, John,Sang, Xiaopeng,Saulnier, Mark,Smith, Daniel,Stefanski, Kevin,Trainor, George,Velaparthi, Upender,Zhang, Guifen,Zimmermann, Kurt,Vyas, Dolatrai M.
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- Synthesis and in vitro evaluation of [18F]BMS-754807: A potential PET ligand for IGF-1R
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Radiosynthesis and in vitro evaluation of [18F](S)-1-(4-((5- cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl) -N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide ([ 18F]BMS-754807 or [18F]1) a specific IGF-1R inhibitor was performed. [18F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield. The radioproduct was obtained in 8% yield by reacting 1a with [ 18F]TBAF in DMSO at 170 C at high radiochemical purity and specific activity (1-2 Ci/μmol, N = 10). The proof of concept of IGF-IR imaging with [18F]1 was demonstrated by in vitro autoradiography studies using pathologically identified surgically removed grade IV glioblastoma, breast cancer and pancreatic tumor tissues. These studies indicate that [ 18F]1 can be a potential PET tracer for monitoring IGF-1R.
- Majo, Vattoly J.,Arango, Victoria,Simpson, Norman R.,Prabhakaran, Jaya,Kassir, Suham A.,Underwood, Mark D.,Bakalian, Mihran,Canoll, Peter,John Mann,Dileep Kumar
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p. 4191 - 4194
(2013/07/19)
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- PYRROLOTRIAZINE KINASE INHIBITORS
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The invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity thereby making them useful as anticancer agents and for the treatment of Alzheimer's Disease.
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