Search

Your search keyword '"Okaniwa M"' showing total 3 results
Start Over Author "Okaniwa M" Topic vascular endothelial growth factor receptor-2
3 results on '"Okaniwa M"'

1. Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives.

Author

Hirose M, Okaniwa M, Miyazaki T, Imada T, Ohashi T, Tanaka Y, Arita T, Yabuki M, Kawamoto T, Tsutsumi S, Sumita A, Takagi T, Sang BC, Yano J, Aertgeerts K, Yoshida S, and Ishikawa T

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, HT29 Cells, Human Umbilical Vein Endothelial Cells drug effects, Humans, Mice, Microsomes drug effects, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemistry, Rats, Rats, Inbred F344, Structure-Activity Relationship, Thiazoles chemical synthesis, Thiazoles chemistry, Vascular Endothelial Growth Factor Receptor-2 metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Drug Design, Neoplasms, Experimental drug therapy, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Thiazoles pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
Abstract

Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
Full Text
View/download PDF

2. 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.

Author

Okaniwa M, Imada T, Ohashi T, Miyazaki T, Arita T, Yabuki M, Sumita A, Tsutsumi S, Higashikawa K, Takagi T, Kawamoto T, Inui Y, Yoshida S, and Ishikawa T

Subjects
Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Crystallography, X-Ray, Dogs, Dose-Response Relationship, Drug, Female, Haplorhini, Humans, Imides administration & dosage, Imides chemical synthesis, Mice, Models, Molecular, Molecular Structure, Prodrugs administration & dosage, Prodrugs chemical synthesis, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemical synthesis, Rats, Rats, Nude, Solubility, Structure-Activity Relationship, Thermodynamics, Vascular Endothelial Growth Factor Receptor-2 metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Drug Design, Imides pharmacology, Prodrugs pharmacology, Protein Kinase Inhibitors pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
Full Text
View/download PDF

3. Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds.

Author

Okaniwa M, Hirose M, Imada T, Ohashi T, Hayashi Y, Miyazaki T, Arita T, Yabuki M, Kakoi K, Kato J, Takagi T, Kawamoto T, Yao S, Sumita A, Tsutsumi S, Tottori T, Oki H, Sang BC, Yano J, Aertgeerts K, Yoshida S, and Ishikawa T

Subjects
Administration, Oral, Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Benzamides pharmacokinetics, Benzamides pharmacology, Benzoates chemical synthesis, Benzoates pharmacokinetics, Benzoates pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cell Line, Tumor, Crystallography, X-Ray, Drug Design, Humans, Imidazoles chemical synthesis, Imidazoles pharmacokinetics, Imidazoles pharmacology, Mice, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Models, Molecular, Molecular Structure, Phosphorylation, Pyridazines chemical synthesis, Pyridazines pharmacokinetics, Pyridazines pharmacology, Rats, Structure-Activity Relationship, Thiazoles pharmacokinetics, Thiazoles pharmacology, Xenograft Model Antitumor Assays, Antineoplastic Agents chemical synthesis, Benzamides chemical synthesis, Bridged Bicyclo Compounds, Heterocyclic chemical synthesis, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Thiazoles chemical synthesis, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
Abstract

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity., (© 2012 American Chemical Society)

Published
2012
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results