title: TIE-2/VEGF-R2 SAR and in vitro activity of C3-acyl dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs.
abstract: Orally bioavailable, dual inhibitors of TIE-2/VEGF-R2 were identified by elaborating the C3/N13 SAR around a fused pyrrolodihydroindazolocarbazole scaffold. Analogs bearing a C3-thiophencarbonyl group were evaluated in enzymatic and cellular biochemical assays; two orally bioavailable analogs were further profiled in functional assays and found to inhibit microvessel growth in rat aortic explant cultures and inhibit Ang-1-stimulated chemotaxis of HUVECs.
authors.affiliation: Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. tunderin@cephalon.com
authors.forename: Ted L
authors.initials: TL
authors.lastname: Underiner
authors.forename: Bruce
authors.initials: B
authors.lastname: Ruggeri
authors.forename: Lisa
authors.initials: L
authors.lastname: Aimone
authors.forename: Mark
authors.initials: M
authors.lastname: Albom
authors.forename: Thelma
authors.initials: T
authors.lastname: Angeles
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hunter
authors.forename: Kurt
authors.initials: K
authors.lastname: Josef
authors.forename: Candy
authors.initials: C
authors.lastname: Robinson
authors.forename: Linda
authors.initials: L
authors.lastname: Weinberg
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.forename: Allison
authors.initials: A
authors.lastname: Zulli
mesh_terms: D000215:Acylation; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000803:Angiotensin I; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001682:Biological Availability; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007191:Indazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008956:Models, Chemical; D051381:Rats; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D007191:Indazoles; D007211:Indoles; D013876:Thiophenes; D000803:Angiotensin I; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2