8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors.
A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure-activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity.
Hudkins
Robert L
RL
Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rhudkins@cephalon.com
Zulli
Allison L
AL
Underiner
Ted L
TL
Angeles
Thelma S
TS
Aimone
Lisa D
LD
Meyer
Sheryl L
SL
Pauletti
Daniel
D
Chang
Hong
H
Fedorov
Elena V
EV
Almo
Steven C
SC
Fedorov
Alexander A
AA
Ruggeri
Bruce A
BA
D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2