Design and synthesis of dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases.
Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.
Dandu
Reddeppareddy
R
Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. dreddy@cephalon.com
Zulli
Allison L
AL
Bacon
Edward R
ER
Underiner
Ted
T
Robinson
Candy
C
Chang
Hong
H
Miknyoczki
Sheila
S
Grobelny
Jennifer
J
Ruggeri
Bruce A
BA
Yang
Shi
S
Albom
Mark S
MS
Angeles
Thelma S
TS
Aimone
Lisa D
LD
Hudkins
Robert L
RL
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006394:Hemangiosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D008546:Melanoma, Experimental / Q000097:blood / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D015394:Molecular Structure; D009389:Neovascularization, Pathologic; D010091:Oximes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014471:Umbilical Veins; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D010091:Oximes; D047428:Protein Kinase Inhibitors; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2