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https://www.readbyqxmd.com/read/28072531/discovery-of-2-1r-4r-4-4-chlorophenyl-phenyl-carbamoyl-oxy-methyl-cyclohexyl-methoxy-acetate-ralinepag-an-orally-active-prostacyclin-receptor-agonist-for-the-treatment-of-pulmonary-arterial-hypertension
#1
Thuy-Anh Tran, Bryan Kramer, Young-Jun Shin, Pureza Vallar, P Douglas Boatman, Ning Zou, Carleton R Sage, Tawfik Gharbaoui, Ashwin Krishnan, Biman Pal, Sagar R Shakya, Antonio Garrido Montalban, John Wesley Adams, Juan Ramirez, Dominic Peter Behan, Anna Shifrina, Anthony Blackburn, Tina Leakakos, Yunqing Shi, Michael Morgan, Abu Sadeque, Weichao Chen, David John Unett, Ibragim Gaidarov, Xiaohua Chen, Steve Chang, Hsin-Hui Shu, Shiu-Feng Tung, Graeme Semple
The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) is described. Detailed profiling of a number of analogues resulted in the identification of 3c (APD811, Ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family, and a more modest 40- 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are superior in vitro to MRE269 (the active metabolite of the clinical compound NS-304) in multiple in vitro measures of IP receptor mediated cAMP signaling...
January 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28065721/the-key-residue-within-the-second-extracellular-loop-of-human-ep3-involved-in-selectively-turning-down-pge2-and-retaining-pge1-mediated-signaling-in-live-cells
#2
Hironari Akasaka, Natasha Thaliachery, Xianghai Zheng, Marissa Blumenthal, Sameer Nikhar, Emma E Murdoch, Qinglan Ling, Ke-He Ruan
Key residues and binding mechanisms of PGE1 and PGE2 on prostanoid receptors are poorly understood due to the lack of X-ray structures for the receptors. We constructed a human EP3 (hEP3) model through integrative homology modeling using the X-ray structure of the β2-adrenergic receptor transmembrane domain and NMR structures of the thromboxane A2 receptor extracellular loops. PGE1 and PGE2 docking into the hEP3 model showed differing configurations within the extracellular ligand recognition site. While PGE2 could form possible binding contact with S211, PGE1 is unable to form similar contacts...
January 5, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28058438/copper-b2pin2-catalyzed-c-h-difluoroacetylation-cycloamidation-of-anilines-leading-to-the-formation-of-3-3-difluoro-2-oxindoles
#3
Miaolin Ke, Qiuling Song
An original and efficient synthesis of 3,3-difluoro-2-oxindole derivatives has been developed via copper/B2pin2-catalyzed difluoroacetylation of aniline via C-H activation followed by intramolecular amidation. In this method, amino groups in primary, secondary or tertiary anilines act as directing groups, providing ortho-difluoroacetylated products regioselectively. And in the first two cases, further intramolecular amidation affords 3,3-difluoro-2-oxindole derivatives via a one-pot strategy. This method facilitates the synthesis of compound A as a potent and selective EP3 receptor antagonist in only five steps in 13% yield instead of the previously reported nine steps in overall 4% yield...
January 6, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28039934/prostaglandin-e2-promotes-hepatic-bile-acid-synthesis-by-an-e-prostanoid-receptor-3-mediated-hepatocyte-nuclear-receptor-4%C3%AE-cholesterol-7%C3%AE-hydroxylase-pathway-in-mice
#4
Shuai Yan, Juan Tang, Yuyao Zhang, Yuanyang Wang, Shengkai Zuo, Yujun Shen, Qianqian Zhang, Di Chen, Yu Yu, Kai Wang, Sheng-Zhong Duan, Ying Yu
: Prostaglandin E2 (PGE2 ) is an important lipid mediator of inflammation. However, whether and how PGE2 regulates hepatic cholesterol metabolism remains unknown. We found that expression of the PGE2 receptor, E prostanoid receptor 3 (EP3) expression is remarkably increased in hepatocytes in response to hyperlipidemic stress. Hepatocyte-specific deletion of EP3 receptor (EP3(hep-/-) ) results in hypercholesterolemia and augments diet-induced atherosclerosis in low-density lipoprotein receptor knockout (Ldlr(-/-) ) mice...
November 5, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27973680/prostaglandin-e2-potentiates-interferon-%C3%AE-induced-nitric-oxide-production-in-cultured-rat-microglia
#5
Takayuki Nagano, Ryo Nishiyama, Ayaka Sanada, Yukiko Mutaguchi, Anna Ioku, Hirohisa Umeki, Satoshi Kishimoto, Daisuke Yamanaka, Shinya H Kimura, Motohiko Takemura
Prostaglandin E2 (PGE2 ) plays crucial roles in managing microglial activation through the prostanoid EP2 receptor, a PGE2 receptor subtype. In the present study, we report that PGE2 enhances interferon-γ (IFN-γ)-induced nitric oxide production in microglia. IFN-γ increased the release of nitrite, a metabolite of nitric oxide, which was augmented by PGE2 , although PGE2 by itself slightly affects nitrite release. The potentiating effect of PGE2 was positively associated with increased expression of inducible nitric oxide synthase...
December 14, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27939158/the-arca-gene-contributes-to-the-serum-resistance-and-virulence-of-haemophilus-parasuis-serovar-13-clinical-strain-ep3
#6
Lingqiang Ding, Xintian Wen, Lvqin He, Xuefeng Yan, Yongping Wen, Sanjie Cao, Xiaobo Huang, Rui Wu, Yiping Wen
As a global transcriptional factor, ArcA regulates the expression of hundreds of genes involved in aerobic and anaerobic metabolism. Here we deleted arcA gene and investigated the biological characteristics of arcA deletion mutant (ΔarcA) in Haemophilus parasuis (H. parasuis) serovar 13 clinical strain EP3. Results indicated that deletion of arcA impaired growth of EP3 strain under anaerobic condition, and reduced virulence of EP3 strain in mice. Additionally, the ΔarcA strain showed greater sensitivity in porcine serum and produced less biofilm mass than the EP3 strain...
November 30, 2016: Veterinary Microbiology
https://www.readbyqxmd.com/read/27913839/the-ability-of-emergency-physicians-to-diagnose-and-score-acute-pancreatitis-on-computed-tomography
#7
A Karagöz, E E Ünlüer, O Oyar, F E Topal, F Topal
PURPOSE: The aim of this study is to determine the ability of emergency physicians' (EP) interpreting contrast-enhanced computed tomographies (CECTs) performed in patients diagnosed or suspected acute pancreatitis (AP), using the modified computed tomography severity index (MCTSI) scoring system. METHODS: This study was conducted in Training and Research Hospital's Emergency Department. From January 1, 2013 to April 30, 2016, patients whom performed CECT within 24 h of admission with diagnosis or suspicion of AP were reviewed retrospectively...
December 2, 2016: European Journal of Trauma and Emergency Surgery: Official Publication of the European Trauma Society
https://www.readbyqxmd.com/read/27770021/in-vivo-studies-validating-multitargeting-of-prostanoid-receptors-for-achieving-superior-anti-inflammatory-effects
#8
David F Woodward, Jenny W Wang, Ming Ni, Alex Bauer, Jose L Martos, Robert W Carling, Neil J Poloso
The purpose of these studies was to test the hypothesis that a selected polypharmacological approach for treating the prostanoid-mediated component of inflammatory diseases would produce a therapeutic effect superior to global inhibition of prostaglandin (PG) biosynthesis by aspirin-like drugs. The compound studied was AGN 211377, which had been previously shown to produce a superior effect on cytokine release from human macrophages compared with cyclooxygenase (COX) inhibitors. AGN 211377 antagonizes prostanoid prostaglandin D2 (DP)1, DP2, prostaglandin E2 (EP)1, EP4, prostaglandin F2α, and thromboxane A2 receptors but not anti-inflammatory EP2, prostaglandin I2, or EP3 receptors...
January 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27763812/prostanoid-receptor-antagonist-effects-on-intraocular-pressure-supported-by-ocular-biodisposition-experiments
#9
David F Woodward, Stacey L Wenthur, Tara L Rudebush, Shan Fan, Carol B Toris
PURPOSE: Since all prostanoid receptors affect intraocular pressure (IOP) and endogenous prostanoids are found in ocular tissues, the pressor effects of prostanoid antagonists were comprehensively evaluated. The absence of effects of most of these antagonists was not entirely anticipated. To ensure no false-negative results, ocular biodisposition studies were conducted. METHODS: Monkeys with laser-induced ocular hypertension were used to study antagonist effects on IOP...
October 20, 2016: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27739618/stimulating-trpv1-externalization-and-synthesis-in-dorsal-root-ganglion-neurons-contributes-to-pge2-potentiation-of-trpv1-activity-and-nociceptor-sensitization
#10
W Ma, B St-Jacques, U Rudakou, Y N Kim
BACKGROUND: Persistent peripheral sensitization contributes to chronic pain. Plasticity of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) induced by pro-inflammatory mediators contributes to sensitization. Prostaglandin E2 (PGE2) enriched in injured tissues is known not only directly to sensitize DRG neurons, but also to potentiate sensitizing effects of other pain mediators such as capsaicin and its receptor transient receptor potential vanilloid-1 (TRPV1). It remains unknown whether PGE2 potentiates TRPV1 activity by stimulating its synthesis, cell surface and axonal trafficking in DRG neurons...
October 14, 2016: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/27711210/signaling-of-prostaglandin-e-receptors-ep3-and-ep4-facilitates-wound-healing-and-lymphangiogenesis-with-enhanced-recruitment-of-m2-macrophages-in-mice
#11
Kanako Hosono, Risa Isonaka, Tadashi Kawakami, Shuh Narumiya, Masataka Majima
Lymphangiogenesis plays an important role in homeostasis, metabolism, and immunity, and also occurs during wound-healing. Here, we examined the roles of prostaglandin E2 (PGE2) receptor (EP) signaling in enhancement of lymphangiogenesis in wound healing processes. The hole-punch was made in the ears of male C57BL/6 mice using a metal ear punch. Healing process and lymphangiogenesis together with macrophage recruitment were analyzed in EP knockout mice. Lymphangiogenesis was up-regulated in the granulation tissues at the margins of punched-hole wounds in mouse ears, and this increase was accompanied by increased expression levels of COX-2 and microsomal prostaglandin E synthase-1...
2016: PloS One
https://www.readbyqxmd.com/read/27688753/systematic-bioinformatic-approach-for-prediction-of-linear-b-cell-epitopes-on-dengue-e-and-prm-protein
#12
Mahesha N Nadugala, Prasad H Premaratne, Charitha L Goonasekara
B-cell epitopes on the envelope (E) and premembrane (prM) proteins of dengue virus (DENV) were predicted using bioinformatics tools, BepiPred, Ellipro, and SVMTriP. Predicted epitopes, 32 and 17 for E and prM proteins, respectively, were then characterized for their level of conservations. The epitopes, EP4/E (48-55), epitope number 4 of E protein at amino acids 48-55, EP9/E (165-182), EP11/E (218-233), EP20/E (322-349), EP21/E (326-353), EP23/E (356-365), and EP25/E (380-386), showed a high intraserotype conservancy with very low pan-serotype conservancy, demonstrating a potential target as serotype specific diagnostic markers...
2016: Advances in Bioinformatics
https://www.readbyqxmd.com/read/27664754/the-ep1-ep3-receptor-agonist-17-pt-pge2-acts-as-an-ep4-receptor-agonist-on-endothelial-barrier-function-and-in-a-model-of-lps-induced-pulmonary-inflammation
#13
Anna Theiler, Viktoria Konya, Lisa Pasterk, Jovana Maric, Thomas Bärnthaler, Ilse Lanz, Wolfgang Platzer, Rufina Schuligoi, Akos Heinemann
Endothelial dysfunction is a hallmark of inflammatory conditions. We recently demonstrated that prostaglandin (PG)E2 enhances the resistance of pulmonary endothelium in vitro and counteracts lipopolysaccharide (LPS)-induced pulmonary inflammation in vivo via EP4 receptors. The aim of this study was to investigate the role of the EP1/EP3 receptor agonist 17-phenyl-trinor-(pt)-PGE2 on acute lung inflammation in a mouse model. In LPS-induced pulmonary inflammation in mice, 17-pt-PGE2 reduced neutrophil infiltration and inhibited vascular leakage...
December 2016: Vascular Pharmacology
https://www.readbyqxmd.com/read/27649982/ocular-hypotensive-effect-of-the-novel-ep3-fp-agonist-ono-9054-versus-xalatan-results-of-a-28-day-double-masked-randomised-study
#14
Eydie Miller Ellis, Michael S Berlin, Caroline L Ward, John A Sharpe, Alam Jamil, Alon Harris
BACKGROUND/AIMS: ONO-9054 is being developed for the reduction of intraocular pressure (IOP) in patients with ocular hypertension (OHT) and open-angle glaucoma (OAG). This study compared the novel dual EP3/FP agonist ONO-9054 with the FP agonist Xalatan. METHODS: Adults (n=123) with bilateral mild/moderate OAG or OHT, with unmedicated IOP of ≥24 mm Hg at 8:00 hours, ≥21 mm Hg at 10:00 hours and ≤36 mm Hg, were randomised 1:1 to receive ONO-9054 (0...
September 20, 2016: British Journal of Ophthalmology
https://www.readbyqxmd.com/read/27631977/cytosolic-and-calcium-independent-phospholipases-a2-activation-and-prostaglandins-e2-are-associated-with-escherichia-coli-induced-reduction-of-insulin-secretion-in-ins-1e-cells
#15
Nunzia Caporarello, Mario Salmeri, Marina Scalia, Carla Motta, Cristina Parrino, Lucia Frittitta, Melania Olivieri, Martina Cristaldi, Roberto Avola, Vincenzo Bramanti, Maria Antonietta Toscano, Carmelina Daniela Anfuso, Gabriella Lupo
It is suspected that microbial infections take part in the pathogenesis of diabetes mellitus type 1 (T1DM). Glucose-induced insulin secretion is accompanied by the release of free arachidonic acid (AA) mainly by cytosolic- and calcium independent phospholipases A2 (cPLA2 and iPLA2). Insulinoma cell line (INS-1E) was infected with E. coli isolated from the blood culture of a patient with sepsis. Invasion assay, Scanning Electron Microscopy and Transmission Electron Microscopy demonstrated the capacity of E. coli to enter cells, which was reduced by PLA2 inhibitors...
2016: PloS One
https://www.readbyqxmd.com/read/27605391/deorphaning-the-macromolecular-targets-of-the-natural-anticancer-compound-doliculide
#16
Gisbert Schneider, Daniel Reker, Tao Chen, Kurt Hauenstein, Petra Schneider, Karl-Heinz Altmann
The cyclodepsipeptide doliculide is a marine natural product with strong actin-polymerizing and anticancer activities. Evidence for doliculide acting as a potent and subtype-selective antagonist of prostanoid E receptor 3 (EP3) is presented. Computational target prediction suggested that this membrane receptor is a likely macromolecular target and enabled immediate in vitro validation. This proof-of-concept study demonstrates the in silico deorphanization of phenotypic screening hits as a viable concept for future natural-product-inspired chemical biology and drug discovery efforts...
September 26, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27581447/periaqueductal-grey-ep3-receptors-facilitate-spinal-nociception-in-arthritic-secondary-hypersensitivity
#17
R A R Drake, J L Leith, F Almahasneh, J Martindale, A W Wilson, B Lumb, L F Donaldson
UNLABELLED: Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase-prostaglandin (PG) E2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27572469/rostral-ventrolateral-medulla-ep3-receptor-mediates-the-sympathoexcitatory-and-pressor-effects-of-prostaglandin-e2-in-conscious-rats
#18
Samar Rezq, Abdel A Abdel-Rahman
Whereas few studies have dealt with the central sympathoexcitatory action of the inflammatory prostanoid prostaglandin E2 (PGE2), there is no information on the expression and cardiovascular function of different PGE2 (EP) receptors in one of the major cardiovascular-regulating nuclei, the rostral ventrolateral medulla (RVLM). The current study aimed at filling this knowledge gap as well as elucidating the implicated molecular mechanisms. To achieve these goals, we showed the expression of EP2, EP3, and EP4 receptors in the RVLM and investigated their cardiovascular roles in conscious rats, ex vivo as well as in cultured PC12 cells...
November 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27557968/the-influence-of-cosolvent-and-heat-on-the-solubility-and-reactivity-of-organophosphorous-pesticide-dnapl-alkaline-hydrolysis
#19
Jens Muff, Leah MacKinnon, Neal D Durant, Lars Frausing Bennedsen, Kirsten Rügge, Morten Bondgaard, Kurt Pennell
The presented research concerned the compatibility of cosolvents with in situ alkaline hydrolysis (ISAH) for treatment of organophosphorous (OPP) pesticide contaminated sites. In addition, the influence of moderate temperature heat increments was studied as a possible enhancement method. A complex dense non-aqueous phase liquid (DNAPL) of primarily parathion (~50 %) and methyl parathion (~15 %) obtained from the Danish Groyne 42 site was used as a contaminant source, and ethanol and propan-2-ol (0, 25, and 50 v/v%) was used as cosolvents in tap water and 0...
August 24, 2016: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/27512093/role-of-the-prostaglandin-e2-receptor-agonists-in-tgf-%C3%AE-1-induced-mesangial-cell-damage
#20
Pe-Ipei Xi, Yu-Yin Xu, Xiao-Lan Chen, Ya-Ping Fan, Jian-Hua Wu
PGE2 exerts its biological effect through binding to various EP receptors that result inactivation of various signal transduction pathways.It also plays an important role in mice glomerular mesangial cells (MCs) damage induced by transforming growth factor-β1 (TGF-β1); however, the molecular mechanisms remain unknown. In present study, we tested the efficacy of four selective agonists of PGE2  receptor, EP1A (17-phenyl trinor prostaglandin E 2:  ethyl amid), EP2A (butaprost), EP3A (sulprostone) and EP4A (cay10580), on mice MCs...
August 10, 2016: Bioscience Reports
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