title: 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.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. dreddy@cephalon.com
authors.forename: Reddeppareddy
authors.initials: R
authors.lastname: Dandu
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zulli
authors.forename: Edward R
authors.initials: ER
authors.lastname: Bacon
authors.forename: Ted
authors.initials: T
authors.lastname: Underiner
authors.forename: Candy
authors.initials: C
authors.lastname: Robinson
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Sheila
authors.initials: S
authors.lastname: Miknyoczki
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grobelny
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D010091:Oximes; D047428:Protein Kinase Inhibitors; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2