Synthesis and evaluation of novel orally active p53–MDM2 interaction inhibitors
| Autor: | Masaki Miyazaki, Yoshinobu Shiose, Masashi Aonuma, Yoshida Keisuke, Haruko Kawato, Mayumi Kitagawa, Hironari Shimizu, Tsunehiko Soga, Hiroyuki Naito, Setsuko Fukutake, Takahiko Seki, Tooru Okayama, Masaya Miyazaki, Yuuichi Sugimoto |
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| Rok vydání: | 2013 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Substituent Administration Oral Pharmaceutical Science Antineoplastic Agents Crystallography X-Ray Biochemistry Pyrrolidine Inhibitory Concentration 50 chemistry.chemical_compound In vivo Oral administration Cell Line Tumor Drug Discovery Humans Proline Molecular Biology Alkyl chemistry.chemical_classification Organic Chemistry Imidazoles Wild type Proto-Oncogene Proteins c-mdm2 Xenograft Model Antitumor Assays In vitro Thiazoles chemistry Drug Design Molecular Medicine Tumor Suppressor Protein p53 Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:4319-4331 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2013.04.056 |
| Popis: | We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53. |
| Databáze: | OpenAIRE |
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