title: Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors.
abstract: A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation.
authors.affiliation: Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. nbecknell@cephalon.com
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Becknell
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zulli
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Candy
authors.initials: C
authors.lastname: Robinson
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002219:Carbamates / Q000737:chemistry*; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D051381:Rats; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D002219:Carbamates; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007191:Indazoles; D014508:Urea; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2