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Bioorg Med Chem. 2007 Sep 1;15(17):5837-44. Epub 2007 Jun 6.

Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors.

Author information

1
Drug Discovery Research, Astellas Pharma Inc, 5-2-3 Tokodai, Tsukuba, Ibaraki, Japan. masahiko.hayakawa@jp.astellas.com

Abstract

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.

PMID:
17601739
DOI:
10.1016/j.bmc.2007.05.070
[Indexed for MEDLINE]

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