To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the BRAF cocrystal structure. Exploration of various [5,6]-fused bicyclic scaffolds resulted in the creation of [1,3]thiazolo[5,4-b]pyridine derivative A  which showed potent inhibitory activity against both RAF and VEGFR2. To improve the oral absorption and the solubility, we designed a novel N-acyl imide prodrug of compound A . N-tert-butoxycarbonyl (Boc)-introduced imide P  was a promising prodrug, which was effectively converted to the active compound A  after its oral administration in animals. Cocrystals of P  with AcOH possessed good physicochemical properties, and showed in vivo antitumor regressive efficacy (T/C = -6.4%) in the A375 human melanoma rat xenograft model. Design, synthesis and characterization of P  will be discussed in detail.

Design and synthesis of novel DFG-out RAF/VEGFR2 inhibitors: Synthesis and characterization of a novel imide-type prodrug for improving oral absorption

243rd National Meeting (2012)

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