title: Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors.
abstract: Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Attempts to optimize a cyclin-dependent kinase-1 (CDK1) inhibitor by using palladium-catalyzed C-C bond, C-N bond formation reactions to assemble diverse biheteroaryl molecules led to the unexpected discovery of a pyrazine-pyridine biheteroaryl as a novel series of potent VEGFR-2 inhibitors. Compound 15, which had IC(50) = 0.084 microM at VEGFR-2, showed very modest selectivity against fibroblast growth factor receptor-2 (IC(50) = 0.21 microM), platelet-derived growth factor receptor (IC(50) = 0.36 microM), and glycogen synthase kinase-3 (IC(50) = 0.478 microM), while it exhibited more than 10-fold selectivity against epidermal growth factor receptor (IC(50) = 1.36 microM) and insulin-R kinase (IC(50) = 1.69 microM). On the other hand, compound 15 exhibited more than 100-fold selectivity against calmodulin kinase 2; casein kinase-1 and -2; CDK1 and -4; mitogen-activated protein kinase; and protein kinase A, Cbeta2, and Cgamma (IC(50) >10 microM). Compound 15 also displayed high inhibitory potency on VEGF-stimulated human umbilical vein endothelial cell (HUVEC) proliferation (IC(50) = 0.005 microM) and good selectivity against cell lines such as HUVEC, human aortic smooth muscle cells, and MRC5 lung fibroblasts. Molecular docking studies were conducted in an attempt to rationalize the unexpected high VEGFR-2 selectivity of 15.
authors.affiliation: Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202, P.O. Box 300, Raritan, New Jersey 08869, USA. gkuo@prdus.jnj.com
authors.forename: Gee-Hong
authors.initials: GH
authors.lastname: Kuo
authors.forename: Aihua
authors.initials: A
authors.lastname: Wang
authors.forename: Stuart
authors.initials: S
authors.lastname: Emanuel
authors.forename: Alan
authors.initials: A
authors.lastname: Deangelis
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Connolly
authors.forename: William V
authors.initials: WV
authors.lastname: Murray
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gruninger
authors.forename: Jan
authors.initials: J
authors.lastname: Sechler
authors.forename: Angel
authors.initials: A
authors.lastname: Fuentes-Pesquera
authors.forename: Dana
authors.initials: D
authors.lastname: Johnson
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
authors.forename: Linda
authors.initials: L
authors.lastname: Jolliffe
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C500067:3-((5-(6-((3-chlorophenyl)amino)pyrazinyl)-3-pyridinyl)amino)-1-propanol; D020533:Angiogenesis Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D011719:Pyrazines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2