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Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors

Marsilje, Thomas, Stutz, Stefan, Boos, Andreas, Niklaus, Michel, Chen, Bei, Jiang, Songchun, Furet, Pascal, Mccarthy, Clive, Stauffer, Frederic, Guagnano, Vito, Vaupel, Andrea, Michellys, Pierre, Schnell, Christian, Jeay, Sebastien and Lu, Wenshuo (2016) Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (8). pp. 2057-2064. ISSN 0960-894X


Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 41 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 41 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumor xenograft model in the mouse.

Item Type: Article
Keywords: Oncology, kinase inhibitor, insulin-like growth factor receptor-1
Date Deposited: 04 Oct 2016 00:45
Last Modified: 04 Oct 2016 00:45


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