Alkynylpyrimidine Amide Derivatives as Potent, Selective, and Orally Active Inhibitors of Tie-2 Kinase

Abstract

The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.

Bidirectional Regulation of Dendritic Voltage-Gated Potassium Channels by the Fragile X Mental Retardation Protein

“…Whereas chemical LTP causes Kv4.2 internalization and redistribution (Cee et al, 2007) and NMDAR activation causes significant reduction of Kv4.2 channels in a reversible manner (Liao et al, 2010), our finding of elevated Kv4.2 levels due to NMDA treatment in the presence of calpain inhibitors, taken together with the luciferase assay showing NMDAR-induced up regulation of translation associated with Kv4.2-3′UTR, strongly suggests that NMDAR activation causes increased production of Kv4.2. Because new protein synthesis is clearly required for long-lasting activity-dependent changes in synaptic transmission, the manner by which neuronal activity engages the translational machinery is key to our understanding of long-term information storage.…”

“…For example, the A-type voltage-gated K + channels (I A ) on the dendrites of CA1 hippocampal pyramidal neurons regulate neuronal signaling by filtering fast synaptic potentials and regulating action potential back propagation, synaptic integration and long-term potentiation (LTP) (Kim and Hoffman, 2008). This I A derives primarily from Kv4.2 (Birnbaum et al, 2004; Cee et al, 2007; Chen et al, 2006). Enriched on the spines of CA1 pyramidal neurons, Kv4.2 is under the regulation of synaptic activity and it in turn contributes to the regulation of synaptic plasticity (Cee et al, 2007; Jung et al, 2008).…”

“…This I A derives primarily from Kv4.2 (Birnbaum et al, 2004; Cee et al, 2007; Chen et al, 2006). Enriched on the spines of CA1 pyramidal neurons, Kv4.2 is under the regulation of synaptic activity and it in turn contributes to the regulation of synaptic plasticity (Cee et al, 2007; Jung et al, 2008). Whether Kv4.2 mRNA is targeted to dendrites to present the opportunity of local regulation by synaptic activity is unknown.…”

“…Whereas the rapid down regulation of Kv4.2 upon N -methyl-D-aspartate receptor (NMDAR) activation due to its internalization and degradation (Cee et al, 2007; Lei et al, 2008; Liao et al, 2010) provides positive feedback to enhance excitation, the dendritic potassium channel level has to quickly recover after a barrage of synaptic activities, given that loss of Kv4.2 function causes enhanced induction of LTP (Chen et al, 2006) while increasing Kv4.2 expression abolishes the ability to induce LTP (Jung et al, 2008). Since alteration of Kv4.2 levels is associated with epilepsy and possibly Alzheimer's disease (Birnbaum et al, 2004) and the KCND2 gene coding for Kv4.2 is near rearrangement breakpoints in autism patients (Scherer et al, 2003), better understanding of the dynamic regulation of Kv4.2 by synaptic activities will help future analyses of the contribution of this potassium channel to neuronal signaling as well as its involvement in neurological and mental disorders.…”

Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2

“…A total of 263 compounds were obtained [13][14][15][16][17][18][19][20][21]. From these compounds a quantitative pharmacophore model was developed with the aid of HypoRefine module within Catalyst [22].…”