1125634-71-0Relevant articles and documents
Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 2. Synthesis and characterization of a novel imide-type prodrug for improving oral absorption
Okaniwa, Masanori,Imada, Takashi,Ohashi, Tomohiro,Miyazaki, Tohru,Arita, Takeo,Yabuki, Masato,Sumita, Akihiko,Tsutsumi, Shunichirou,Higashikawa, Keiko,Takagi, Terufumi,Kawamoto, Tomohiro,Inui, Yoshitaka,Yoshida, Sei,Ishikawa, Tomoyasu
experimental part, p. 4680 - 4692 (2012/09/08)
As an alternative to the previously reported solid dispersion formulation for enhancing the oral absorption of thiazolo[5,4-b]pyridine 1, we investigated novel N-acyl imide prodrugs of 1 as RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. Introducing N-acyl promoieties at the benzanilide position gave chemically stable imides. N-tert-Butoxycarbonyl (Boc) introduced imide 6 was a promising prodrug, which was converted to the active compound 1 after its oral administration in mice. Cocrystals of 6 with AcOH (6b) possessed good physicochemical properties with moderate thermodynamic solubility (19 μg/mL). This crystalline prodrug 6b was rapidly and enzymatically converted into 1 after its oral absorption in mice, rats, dogs, and monkeys. Prodrug 6b showed in vivo antitumor regressive efficacy (T/C = -6.4%) in an A375 melanoma xenograft model in rats. Hence, we selected 6b as a promising candidate and are performing further studies. Herein, we report the design, synthesis, and characterization of novel imide-type prodrugs.
