Optimization of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine inhibitors of IGF-1R : Elimination of an acid-mediated decomposition pathway

Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1') carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with t...

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Published in:Bioorganic & medicinal chemistry letters 2009-01, Vol.19 (2), p.373-377
Main Authors: CHAMBERLAIN, Stanley D, REDMAN, Aniko M, STEVENS, Kirk L, WILSON, Joseph W, BRAD SHOTWELL, J, PATNAIK, Samarjit, BRICKHOUSE, Keith, CHEW, Yen-Chiat, DEANDA, Felix, GERDING, Roseanne, HUANGSHU LEI, MOORTHY, Ganesh, PATRICK, Mark
Format: Article
Language:English
Subjects:
Acids - chemistry
Antineoplastic agents
Biological and medical sciences
General aspects
Medical sciences
Pharmacology. Drug treatments
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Pyrimidines - chemistry
Pyrimidines - pharmacology
Pyrroles - chemistry
Pyrroles - pharmacology
Receptor, IGF Type 1 - antagonists & inhibitors
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Summary:Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1') carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1') carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2008.11.065