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
| Autor: | Sei Yoshida, Takeo Arita, Masato Yabuki, Terufumi Takagi, Tomohiro Kawamoto, Shunichirou Tsutsumi, Tomoyasu Ishikawa, Masanori Okaniwa, Akihiko Sumita, Tomohiro Ohashi, Takashi Imada, Tohru Miyazaki, Bi-Ching Sang, Yuta Tanaka, Jason Yano, Masaaki Hirose, Kathleen Aertgeerts |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Pyrimidine Stereochemistry Clinical Biochemistry Substituent Pharmaceutical Science Antineoplastic Agents Crystallography X-Ray Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship Microsomes Drug Discovery Human Umbilical Vein Endothelial Cells Structure–activity relationship Animals Humans Solubility Molecular Biology Protein Kinase Inhibitors Cell Proliferation Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Kinase insert domain receptor Neoplasms Experimental Vascular Endothelial Growth Factor Receptor-2 Xenograft Model Antitumor Assays Rats Inbred F344 Rats Thiazoles Drug Design Molecular Medicine Amine gas treating Lead compound Linker HT29 Cells |
| Zdroj: | Bioorganicmedicinal chemistry. 20(18) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect