Discovery of DS-5272 as a promising candidate: A potent and orally active p53-MDM2 interaction inhibitor
| Autor: | Hiroyuki Naito, Yoshida Keisuke, Yuuichi Sugimoto, Tsunehiko Soga, Haruko Kawato, Masaki Miyazaki, Takahiko Seki, Setsuko Fukutake, Tooru Okayama, Kouichi Uoto, Masaya Miyazaki, Masashi Aonuma, Mayumi Kitagawa |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Pyrrolidines Stereochemistry Clinical Biochemistry Substituent Pharmaceutical Science Administration Oral Gene Expression Mice Nude Antineoplastic Agents Bone Neoplasms Biochemistry Pyrrolidine chemistry.chemical_compound Mice Oral administration Cell Line Tumor Drug Discovery Potency Animals Humans Cytotoxicity Molecular Biology Octane Cell Proliferation Mice Inbred BALB C Organic Chemistry Imidazoles Proto-Oncogene Proteins c-mdm2 Sarcoma Fluorine Xenograft Model Antitumor Assays Piperazine Thiazoles chemistry Molecular Medicine Tumor Suppressor Protein p53 Lead compound Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry. 23(10) |
| ISSN: | 1464-3391 |
| Popis: | We have published p53-MDM2 interaction inhibitors possessing a novel dihydroimidazothiazole scaffold. Although our lead compound 1 showed strong antitumor activity with single oral administration on a xenograft model using MV4-11 cells harboring wild-type p53, it needed a higher dose (200mg/kg) for distinct efficacy. We executed further optimization with the aim of improvement of potency and physicochemical properties. Thus optimal compounds were furnished by introducing fluorine moieties onto the phenyl ring at the C-6 position and the pyrrolidine part at the C-2 substituent; and modifying the terminal piperazine to 4,7-diazaspiro[2,5]octane variants. Furthermore, replacing 4-chlorophenyl on the C-5 position with pyridyl variant decreased nonspecific cytotoxicity significantly. Our exploration afforded DS-5272 indicating excellent antitumor efficacy from a dose of 25mg/kg on SJSA-1 xenografted models with high safety and good PK profiles, which has appropriate potency as a clinical candidate. |
| Databáze: | OpenAIRE |
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