The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells

be activated by protons in the inflamed tissue microenvironment. Herein, we report that acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelialcells through the Ga12/13/Rho GTPase signaling pathway. Evaluation of GPR4 in the inflammatoryresponse using the acute hindlimb ischemia-reperfusion mouse model revealed that GPR4 mediatestissue edema, inflammatory exudate formation, endothelial adhesion molecule expression, and leuko-cyte infiltration in the inflamed tissue. Genetic knockout and pharmacologic inhibition of GPR4alleviate tissue inflammation. These results suggest GPR4 is a pro-inflammatory receptor and couldbe targeted for therapeutic intervention

Synthesis of 3-chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and its derivatives.

Synthesis of novel 3-Chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and its derivatives using sequentional ortho-formylation/ortho-allylation reaction of 2-chloro-3-fluoropyridine and ring-closing metathesis is described

Palladium-Catalyzed Cyanomethylation of Aryl Halides through Domino Suzuki Coupling-Isoxazole Fragmentation.

A one-pot protocol for the cyanomethylation of aryl halides through a palladium-catalyzed reaction with isoxazole-4-boronic acid pinacol ester was developed. Mechanistically, the reaction proceeds through (1) Suzuki coupling, (2) base-induced fragmentation, and (3) deformylation as shown by characterization of all postulated intermediates. Under optimized conditions (PdCl(2)dppf, KF, DMSO/H(2)O, 130 °C) a broad spectrum of aryl bromides could be converted into arylacetonitriles with up to 88% yield

Pharmacological Inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model

Inflammatory bowel disease (IBD) is characterized by chronic, recurring inflammation of the digestive tract. Current therapeutic approaches are limited and include biologics and steroids such as anti-TNFα monoclonal antibodies and corticosteroids, respectively. Significant adverse drug effects can occur for chronic usage and include increased risk of infection in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. We have assessed the effects of a GPR4 antagonist, 2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE 52-QQ57) in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. The clinical parameters such as body weight loss and fecal score were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control. Macroscopic disease indicators such as colon shortening, splenic expansion, and mesenteric lymph node enlargement were all reduced in severity in the GPR4 antagonist 13 treated mice. Histopathological features of active colitis were alleviated in GPR4 antagonist 13 treatment groups compared to vehicle control. Finally, inflammatory gene expression in the colon tissues and vascular adhesion molecule expression in the intestinal endothelia were attenuated by GPR4 antagonist 13. Our results indicate that GPR4 antagonist 13 provides a protective effect in the DSS-induced acute colitis mouse model, and inhibition of GPR4 can be explored as a novel anti-inflammatory approach

Modulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral Exposure.

MK2, MAP-activated protein kinase 2, plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential in the treatment of inflammation and cancer, up to date no MK2 low molecular weight inhibitor reached the clinic, mainly because of inadequate ADME properties of the developed inhibitors. In this paper we describe an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochemical and ADME properties. While keeping the target potency, the novel fluoro-derivatives showed not only improved permeability but also enhanced solubility and reduced in vivo clearance leading to significantly increased oral exposure

Nucleoside Analogues with a 1,3-Diene-Fe(CO)(3) Substructure: Stereoselective Synthesis, Configurational Assignment, and Apoptosis-Inducing Activity

The synthesis and stereochemical assignment of two classes of iron-containing nucleoside analogues, both of which contain a butadieneFe(CO)(3) substructure, is described. The first type of compounds are Fe(CO)(3)-complexed 3-alkenyl-2,3-dideoxy-2,3-dehydro nucleosides (2,5-dihydrofuran derivatives), from which the second class of compounds is derived by formal replacement of the ring oxygen atom by a CH2 group (carbocyclic nucleoside analogues). These compounds were prepared in a stereoselective manner through the metal-assisted introduction of the nucleobase. Whilst the furanoid intermediates were prepared from carbohydrates (such as methyl-glucopyranoside), the carbocyclic compounds were obtained by using an intramolecular Pauson-Khand reaction. Stereochemical assignments based on NMR and CD spectroscopy were confirmed by X-ray structural analysis. Biological investigations revealed that several of the complexes exhibited pronounced apoptosis-inducing properties (through an unusual caspase 3-independent but ROS-dependent pathway). Furthermore, some structure-activity relationships were identified, also as a precondition for the design and synthesis of fluorescent and biotin-labeled conjugates

Pyrrolo-pyrimidones: a novel class of MK2 inhibitors with potent cellular activity.

Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases

Novel 3-Aminopyrazole Inhibitors of MK-2 Discovered by Scaffold Hopping Strategy

New, selective 3-aminopyrazole based MK2-inhibitors were discovered by scaffold hopping strategy. The new derivatives proved to inhibit intracellular phosphorylation of hsp27 as well as LPS-induced TNFa release in cells. In addition, selected derivative 14e also inhibited LPS-induced TNFa release in vivo

Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis

GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain