Isothiazolopyrimidines and isoxazolopyrimidines as novel multi-targeted inhibitors of receptor tyrosine kinases.
A series of isothiazolopyrimidines and isoxazolopyrimidines were synthesized and identified as potent KDR inhibitors. SAR studies led to isothiazolopyrimidine urea analogs that potently inhibit VEGFR tyrosine kinases (KDR enzymatic and cellular IC(50) values below 10 nM) as well as cKIT and TIE2. The selected compounds 8 and 13 display 56% and 48% oral bioavailability in mice, respectively.
Ji
Zhiqin
Z
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6100, USA. zhiqin.ji@abbott.com
Ahmed
Asma A
AA
Albert
Daniel H
DH
Bouska
Jennifer J
JJ
Bousquet
Peter F
PF
Cunha
George A
GA
Glaser
Keith B
KB
Guo
Jun
J
Li
Junling
J
Marcotte
Patrick A
PA
Moskey
Maria D
MD
Pease
Lori J
LJ
Stewart
Kent D
KD
Yates
Melinda
M
Davidsen
Steven K
SK
Michaelides
Michael R
MR
D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D042787:Receptor, TIE-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D004791:Enzyme Inhibitors; D011743:Pyrimidines; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1