Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110α inhibitors
| Autor: | Hiroyuki Kaizawa, Kenichi Kawaguchi, Michael D. Waterfield, Mitsuaki Ohta, Mayumi Yamano, Tomonobu Koizumi, Takahide Ohishi, Shin-ichi Tsukamoto, Florence I. Raynaud, Masahiko Hayakawa, Minoru Okada, Peter J. Parker, Paul Workman |
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| Rok vydání: | 2007 |
| Předmět: |
Pyridines
Stereochemistry Clinical Biochemistry Nitro compound Pharmaceutical Science Hydrazone Pyrazole Biochemistry Chemical synthesis Inhibitory Concentration 50 Mice Phosphatidylinositol 3-Kinases Structure-Activity Relationship chemistry.chemical_compound In vivo Cell Line Tumor Drug Discovery Animals Humans Structure–activity relationship Protein Kinase Inhibitors Molecular Biology Cell Proliferation Phosphoinositide-3 Kinase Inhibitors chemistry.chemical_classification Molecular Structure biology Organic Chemistry Hydrazones Imidazoles Temperature Biological activity Xenograft Model Antitumor Assays Enzyme Activation Isoenzymes Protein Subunits chemistry Enzyme inhibitor biology.protein Molecular Medicine Sulfur |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:5837-5844 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2007.05.070 |
| Popis: | We have previously reported the imidazo[1,2-a]pyridine derivative 4 as a novel p110alpha inhibitor; however, although 4 is a potent inhibitor of p110alpha enzymatic activity and tumor cell proliferation in vitro, it is unstable in solution and ineffective in vivo. To increase stability the pyrazole of 4 was replaced with a hydrazone and a moderately potent p110alpha inhibitor 7a was obtained. Subsequent optimization of 7a afforded exceptionally potent p110alpha inhibitors, including 8c and 8h, with IC(50) values of 0.30 nM and 0.26 nM, respectively; to the best of our knowledge, these compounds are the most potent PI3K p110alpha inhibitors reported to date. Compound 8c was also stable in solution and exhibited significant anti-tumor effectiveness in vivo. |
| Databáze: | OpenAIRE |
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