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Scaffold oriented synthesis. Part 2: Design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors.

Gracias V, Ji Z, Akritopoulou-Zanze I, Abad-Zapatero C, Huth JR, Song D, Hajduk PJ, Johnson EF, Glaser KB, Marcotte PA, Pease L, Soni NB, Stewart KD, Davidsen SK, Michaelides MR, Djuric SW

Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60044, USA.

We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).

Published 15 April 2008 in Bioorg Med Chem Lett, 18(8): 2691-5.
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