title: Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Fairhurst
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Marsilje
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stutz
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Boos
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Niklaus
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Songchun
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Wenshuo
authors.initials: W
authors.lastname: Lu
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Clive
authors.initials: C
authors.lastname: McCarthy
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Stauffer
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Vito
authors.initials: V
authors.lastname: Guagnano
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vaupel
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jeay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; C000612663:5-(3-phenyl-(2-cyclic-ether)-methyl-ether)-4-aminopyrrolopyrimidine; D000970:Antineoplastic Agents; D007093:Imidazoles; C501177:NVP-AEW541; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1
keywords: Insulin-like growth factor receptor-1; Kinase inhibitor; Oncology