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 |
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| Authors: | Stanley D. Chamberlain Anikó M. Redman Samarjit Patnaik Keith Brickhouse Yen-Chiat Chew Felix Deanda Roseanne Gerding Huangshu Lei Ganesh Moorthy Mark Patrick Kirk L. Stevens Joseph W. Wilson J. Brad Shotwell |
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| Affiliation: | 1. GlaxoSmithKline, Oncology R&D, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, USA;2. GlaxoSmithKline, Computational and Structural Chemistry, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, USA;3. GlaxoSmithKline, Oncology R&D, 1250 S. Collegeville Road, Collegeville, PA 19426, USA;4. GlaxoSmithKline, Physical Properties and Developability, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, USA |
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| Abstract: | 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. |
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