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

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

  • Bioorg Med Chem Lett. 2016 Apr 15;26(8):2057-64. doi: 10.1016/j.bmcl.2016.02.075.
Robin A Fairhurst 1,  Thomas H Marsilje 2,  Stefan Stutz 3,  Andreas Boos 3,  Michel Niklaus 3,  Bei Chen 2,  Songchun Jiang 2,  Wenshuo Lu 2,  Pascal Furet 3,  Clive McCarthy 3,  Frédéric Stauffer 3,  Vito Guagnano 3,  Andrea Vaupel 3,  Pierre-Yves Michellys 2,  Christian Schnell 3,  Sébastien Jeay 3
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
  • 2 Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
  • 3 Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
PMID: 26951753 DOI: 10.1016/j.bmcl.2016.02.075
Abstract

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 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 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 tumour xenograft model in the mouse.

Keywords

Insulin-like growth factor receptor-1; Kinase inhibitor; Oncology.

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