title: Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent.
abstract: A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.
authors.affiliation: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States. rhudkins@cephalon.com
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Becknell
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zulli
authors.forename: Ted L
authors.initials: TL
authors.lastname: Underiner
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Miknyoczki
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hunter
authors.forename: Susan
authors.initials: S
authors.lastname: Jones-Bolin
authors.forename: Hugh
authors.initials: H
authors.lastname: Zhao
authors.forename: Edward R
authors.initials: ER
authors.lastname: Bacon
authors.forename: John P
authors.initials: JP
authors.lastname: Mallamo
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002227:Carbazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: C571190:11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo(5,4-a)pyrrolo(3,4-c)carbazol-4-one; D020533:Angiogenesis Inhibitors; D002227:Carbazoles; D007191:Indazoles; D011994:Recombinant Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3