title: Identification and characterization of small-molecule inhibitors of Tie2 kinase.
abstract: Angiopoietins and Tie2 receptor were recently identified as an endothelial cell-specific ligand-receptor system that is critical for vascular development and postnatal pathologic angiogenesis by mediating vascular integrity. In this study, we identified a series of small-molecule Tie2 inhibitors, which blocked Ang1-induced Tie2 autophosphorylation and downstream signaling with an IC(50) value at 0.3 microM. Further optimization yields improved selectivity, aqueous solubility, microsomal stability and cytochrome P450 profile for one of the compounds (compound 7). Both compound 1 and compound 7 inhibit endothelial cell tube formation. Furthermore, in a rat model of Matrigel-induced choroidal neovascularization, compound 7 significantly diminished aberrant vessel growth. Our findings demonstrate a potential clinical benefit by specifically targeting Tie2-mediated angiogenic disorders.
authors.affiliation: Department of Biology, Pharmacopeia Inc, Cranbury, NJ 08512, USA. jliu@pcop.com
authors.forename: Jinqi
authors.initials: J
authors.lastname: Liu
authors.forename: Tsung H
authors.initials: TH
authors.lastname: Lin
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cole
authors.forename: Rong
authors.initials: R
authors.lastname: Wen
authors.forename: Lian
authors.initials: L
authors.lastname: Zhao
authors.forename: Marc-Raleigh
authors.initials: MR
authors.lastname: Brescia
authors.forename: Biji
authors.initials: B
authors.lastname: Jacob
authors.forename: Zahid
authors.initials: Z
authors.lastname: Hussain
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Appell
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.forename: Maria L
authors.initials: ML
authors.lastname: Webb
mesh_terms: D042683:Angiopoietin-1 / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002829:Choroid / Q000098:blood supply / Q000473:pathology; D020256:Choroidal Neovascularization / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects
chemical_list: D042683:Angiopoietin-1; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D042787:Receptor, TIE-2