Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity

Stanley D Chamberlain; Anikó M Redman; Joseph W Wilson; Felix Deanda; J Brad Shotwell; Roseanne Gerding; Huangshu Lei; Bin Yang; Kirk L Stevens; Anne M Hassell; Lisa M Shewchuk; M Anthony Leesnitzer; Jeffery L Smith; Peter Sabbatini; Charity Atkins; Arthur Groy; Jason L Rowand; Rakesh Kumar; Robert A Mook Jr; Ganesh Moorthy; Samarjit Patnaik

doi:10.1016/j.bmcl.2008.11.077

Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity

Bioorg Med Chem Lett. 2009 Jan 15;19(2):360-4. doi: 10.1016/j.bmcl.2008.11.077. Epub 2008 Nov 24.

Affiliation

¹ GlaxoSmithKline, Oncology R&D, 5 Moore Drive, Research Triangle Park, NC 27709, USA.

PMID: 19071018
DOI: 10.1016/j.bmcl.2008.11.077

Abstract

The SAR of C5' functional groups with terminal basic amines at the C6 aniline of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines is reported. Examples demonstrate potent inhibition of IGF-1R with 1000-fold selectivity over JNK1 and 3 in enzymatic assays.

MeSH terms

MAP Kinase Kinase 4 / antagonists & inhibitors*
Models, Molecular
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrroles / chemistry
Pyrroles / pharmacology*
Receptor, IGF Type 1 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

4,6-bis-anilino-1H-pyrrolo(2,3-d)pyrimidine
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Receptor, IGF Type 1
MAP Kinase Kinase 4