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

Robin A Fairhurst; Thomas H Marsilje; Stefan Stutz; Andreas Boos; Michel Niklaus; Bei Chen; Songchun Jiang; Wenshuo Lu; Pascal Furet; Clive McCarthy; Frédéric Stauffer; Vito Guagnano; Andrea Vaupel; Pierre-Yves Michellys; Christian Schnell; Sébastien Jeay

doi:10.1016/j.bmcl.2016.02.075

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. Epub 2016 Feb 26.

Authors

Robin A Fairhurst¹, Thomas H Marsilje², Stefan Stutz³, Andreas Boos³, Michel Niklaus³, Bei Chen², Songchun Jiang², Wenshuo Lu², Pascal Furet³, Clive McCarthy³, Frédéric Stauffer³, Vito Guagnano³, Andrea Vaupel³, Pierre-Yves Michellys², Christian Schnell³, Sébastien Jeay³

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Mice
Mice, Nude
Molecular Structure
NIH 3T3 Cells
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazines / chemical synthesis
Pyrazines / chemistry
Pyrazines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Receptor, IGF Type 1 / antagonists & inhibitors*
Receptor, IGF Type 1 / metabolism
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
5-(3-phenyl-(2-cyclic-ether)-methyl-ether)-4-aminopyrrolopyrimidine
Antineoplastic Agents
Imidazoles
NVP-AEW541
Protein Kinase Inhibitors
Pyrazines
Pyrimidines
Pyrroles
Receptor, IGF Type 1