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

Robert L Hudkins; Nadine C Becknell; Allison L Zulli; Ted L Underiner; Thelma S Angeles; Lisa D Aimone; Mark S Albom; Hong Chang; Sheila J Miknyoczki; Kathryn Hunter; Susan Jones-Bolin; Hugh Zhao; Edward R Bacon; John P Mallamo; Mark A Ator; Bruce A Ruggeri

doi:10.1021/jm201449n

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

J Med Chem. 2012 Jan 26;55(2):903-13. doi: 10.1021/jm201449n. Epub 2012 Jan 6.

Authors

Robert L Hudkins¹, Nadine C Becknell, Allison L Zulli, Ted L Underiner, Thelma S Angeles, Lisa D Aimone, Mark S Albom, Hong Chang, Sheila J Miknyoczki, Kathryn Hunter, Susan Jones-Bolin, Hugh Zhao, Edward R Bacon, John P Mallamo, Mark A Ator, Bruce A Ruggeri

Affiliation

¹ Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States. rhudkins@cephalon.com

PMID: 22148921
DOI: 10.1021/jm201449n

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.

MeSH terms

Administration, Oral
Angiogenesis Inhibitors / chemical synthesis*
Angiogenesis Inhibitors / pharmacokinetics
Angiogenesis Inhibitors / pharmacology
Animals
Biological Availability
Carbazoles / chemical synthesis*
Carbazoles / pharmacokinetics
Carbazoles / pharmacology
Humans
Indazoles / chemical synthesis*
Indazoles / pharmacokinetics
Indazoles / pharmacology
Macaca fascicularis
Male
Mice
Mice, Nude
Models, Molecular
Neovascularization, Physiologic / drug effects
Rats
Rats, Sprague-Dawley
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
Receptor, TIE-2 / antagonists & inhibitors*
Receptor, TIE-2 / chemistry
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / chemistry
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / chemistry
Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors
Xenograft Model Antitumor Assays

Substances

11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo(5,4-a)pyrrolo(3,4-c)carbazol-4-one
Angiogenesis Inhibitors
Carbazoles
Indazoles
Recombinant Proteins
Receptor, Fibroblast Growth Factor, Type 1
Receptor, TIE-2
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor-3