Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors.
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.
Hayakawa
Masahiko
M
Drug Discovery Research, Astellas Pharma Inc, 5-2-3 Tokodai, Tsukuba, Ibaraki, Japan. masahiko.hayakawa@jp.astellas.com
Kawaguchi
Ken-Ichi
K
Kaizawa
Hiroyuki
H
Koizumi
Tomonobu
T
Ohishi
Takahide
T
Yamano
Mayumi
M
Okada
Minoru
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-Ichi
S
Raynaud
Florence I
FI
Parker
Peter
P
Workman
Paul
P
Waterfield
Michael D
MD
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
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