title: Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors.
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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc, 5-2-3 Tokodai, Tsukuba, Ibaraki, Japan. masahiko.hayakawa@jp.astellas.com
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kawaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaizawa
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Koizumi
authors.forename: Takahide
authors.initials: T
authors.lastname: Ohishi
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamano
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Peter
authors.initials: P
authors.lastname: Parker
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Waterfield
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry*; D013696:Temperature; D023041:Xenograft Model Antitumor Assays
chemical_list: D006835:Hydrazones; D007093:Imidazoles; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D011725:Pyridines; D013455:Sulfur; C029899:imidazole; C023666:pyridine