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

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

  • Bioorg Med Chem. 2007 Sep 1;15(17):5837-44. doi: 10.1016/j.bmc.2007.05.070.
Masahiko Hayakawa 1,  Ken-Ichi Kawaguchi,  Hiroyuki Kaizawa,  Tomonobu Koizumi,  Takahide Ohishi,  Mayumi Yamano,  Minoru Okada,  Mitsuaki Ohta,  Shin-Ichi Tsukamoto,  Florence I Raynaud,  Peter Parker,  Paul Workman,  Michael D Waterfield
Affiliations

Affiliation

  • 1 Drug Discovery Research, Astellas Pharma Inc, 5-2-3 Tokodai, Tsukuba, Ibaraki, Japan. masahiko.hayakawa@jp.astellas.com
PMID: 17601739 DOI: 10.1016/j.bmc.2007.05.070
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.

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