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
  • 1. Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: [email protected].
  • 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.