title: 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.
abstract: 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 (19μg/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.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. masanori.okaniwa@takeda.com
authors: Masanori
authors: M
authors: Okaniwa
authors: Takashi
authors: T
authors: Imada
authors: Tomohiro
authors: T
authors: Ohashi
authors: Tohru
authors: T
authors: Miyazaki
authors: Takeo
authors: T
authors: Arita
authors: Masato
authors: M
authors: Yabuki
authors: Akihiko
authors: A
authors: Sumita
authors: Shunichirou
authors: S
authors: Tsutsumi
authors: Keiko
authors: K
authors: Higashikawa
authors: Terufumi
authors: T
authors: Takagi
authors: Tomohiro
authors: T
authors: Kawamoto
authors: Yoshitaka
authors: Y
authors: Inui
authors: Sei
authors: S
authors: Yoshida
authors: Tomoyasu
authors: T
authors: Ishikawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D000882:Haplorhini; D006801:Humans; D007094:Imides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007094:Imides; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2