Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110alpha inhibitors.
3-{1-[(4-Fluorophenyl)sulfonyl]-1H-pyrazol-3-yl}-2-methylimidazo[1,2-a]pyridine, 2a, was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 0.67microM, through screening in a scintillation proximity assay. Optimization of the substituents of 2a increased the p110alpha inhibitory activity by more than 300-fold (2g: IC(50)=0.0018microM). Further structural modification of 2g afforded thiazole derivative 12, which has potent p110alpha inhibitory activity (IC(50) of 0.0028microM) and is highly selective for p110alpha over other PI3K isoforms. Compound 12 also inhibited serum-induced cell proliferation of A375 and HeLa cells in vitro with IC(50) values of 0.14microM and 0.21microM, respectively, and suppressed tumor growth by 37% in a mouse HeLa xenograft model when dosed intraperitoneally at 25mg/kg. These results suggest that selective p110alpha inhibitors may have potential as cancer therapeutic agents.
Hayakawa
Masahiko
M
Institute for Drug Discovery Research, Astellas Pharma Inc., 5-2-3 Tokodai, Tsukuba, Ibaraki 300-2698, Japan. masahiko.hayakawa@jp.astellas.com
Kaizawa
Hiroyuki
H
Kawaguchi
Ken-Ichi
K
Ishikawa
Noriko
N
Koizumi
Tomonobu
T
Ohishi
Takahide
T
Yamano
Mayumi
M
Okada
Minoru
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-Ichi
S
Raynaud
Florence I
FI
Waterfield
Michael D
MD
Parker
Peter
P
Workman
Paul
P
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C001439:imidazo(1,2-a)pyridine