Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110α inhibitors

We have previously reported the imidazo[1,2-a]pyridine derivative 4 as a novel p110 alpha inhibitor; however, although 4 is a potent inhibitor of p110 alpha 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 p110 alpha inhibitor 7a was obtained. Subsequent optimization of 7a afforded exceptionally potent p110 alpha 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 p110 alpha inhibitors reported to date. Compound 8c was also stable in solution and exhibited significant anti-tumor effectiveness in vivo. (c) 2007 Elsevier Ltd. All rights reserved.