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
| Autor: | Tomohiro Ohashi, Shunichirou Tsutsumi, Masanori Okaniwa, Masato Yabuki, Tomoyasu Ishikawa, Akihiko Sumita, Terufumi Takagi, Takashi Imada, Takeo Arita, Tohru Miyazaki, Tomohiro Kawamoto, Keiko Higashikawa, Yoshitaka Inui, Sei Yoshida |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Stereochemistry Clinical Biochemistry Pharmaceutical Science Administration Oral Antineoplastic Agents Absorption (skin) Crystallography X-Ray Imides Biochemistry chemistry.chemical_compound Mice Rats Nude Structure-Activity Relationship Dogs Oral administration In vivo Cell Line Tumor Drug Discovery Animals Humans Prodrugs Solubility Imide Molecular Biology Protein Kinase Inhibitors Dose-Response Relationship Drug Molecular Structure Organic Chemistry Kinase insert domain receptor Benzanilide Haplorhini Prodrug Vascular Endothelial Growth Factor Receptor-2 Xenograft Model Antitumor Assays Rats chemistry Drug Design Molecular Medicine Thermodynamics Female |
| Zdroj: | Bioorganicmedicinal chemistry. 20(15) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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