Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors

Gee-Hong Kuo, Aihua Wang, Stuart Emanuel, Alan Deangelis, Rui Zhang, Peter J Connolly, William V Murray, Robert H Gruninger, Jan Sechler, Angel Fuentes-Pesquera, Dana Johnson, Steven A Middleton, Linda Jolliffe, Xin Chen
Journal of medicinal chemistry · 2005 · doi:10.1021/jm040099a · PMID:15771433
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A novel series of pyrazine-pyridine biheteroaryl compounds were synthesized and found to be potent inhibitors of vascular endothelial growth factor receptor-2, with compound 15 showing strong selectivity against multiple kinases and cell types.

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The paper reports the synthesis and discovery of pyrazine-pyridine biheteroaryl compounds developed as inhibitors of vascular endothelial growth factor receptor-2 (VEGFR2), starting from reported enzyme hit compounds and testing multiple ligand-target pairs. VEGFR2 enzyme inhibition was measured using an assay with a biotinylated peptide substrate and ATP/[γ-33P]ATP at pH 8.0, yielding a range of IC50 values across tested compounds (including values as low as 84 nM and many at 1,000 nM or higher). A major caveat evident from the presented content is that the provided excerpt is largely limited to affinity/IC50-style results without broader in vitro/in vivo efficacy, selectivity, or pharmacokinetic context. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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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.
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Report error Found 30 Enz. Inhib. hit(s) with all data for entry = 830 Affinity DataIC50: 84nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 210nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 360nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 478nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 497nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 500nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 500nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 708nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 761nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.36E+3nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.69E+3nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 2.11E+3nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 2.22E+3nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 2.40E+3nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 8.08E+3nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMpH: 8.0 T: 2°CAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:The enzyme was assayed with a biotinylated peptide substrate and test compounds in the presence of 5 uM ATP/[gamma-33P]ATP in a streptavidin coated F...More data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

Angiogenesis Inhibitors Heterocyclic Compounds, 2-Ring Pyrazines Pyridines Vascular Endothelial Growth Factor Receptor-2 Angiogenesis Inhibitors Angiogenesis Inhibitors Angiogenesis Inhibitors Cell Proliferation Cell Proliferation Cells, Cultured Endothelial Cells Endothelial Cells Endothelial Cells Fibroblasts Fibroblasts Fibroblasts Heterocyclic Compounds, 2-Ring Heterocyclic Compounds, 2-Ring Heterocyclic Compounds, 2-Ring

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