Chamberlain Stanley D, Redman Anikó M, Patnaik Samarjit, Brickhouse Keith, Chew Yen-Chiat, Deanda Felix, Gerding Roseanne, Lei Huangshu, Moorthy Ganesh, Patrick Mark, Stevens Kirk L, Wilson Joseph W, Brad Shotwell J
GlaxoSmithKline, Oncology R&D, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, USA.
Bioorg Med Chem Lett. 2009 Jan 15;19(2):373-7. doi: 10.1016/j.bmcl.2008.11.065. Epub 2008 Nov 24.
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.
对一系列4,6-双苯胺基-1H-吡咯并[2,3-d]嘧啶的初步评估显示，C(1')羧酰胺对于体外抑制IGF-1R的亚微摩尔效力而言是优选的。随后对化合物1进行的溶液稳定性研究揭示了其C(1')羧酰胺对酸诱导的分子内环化的敏感性。在此，我们描述了几种在4,6-双苯胺基-1H-吡咯并[2,3-d]嘧啶模板内生成高效且酸稳定的IGF-1R抑制剂的成功方法。
