Publications by authors named "Thota Ganesh"

48 Publications

A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats.

Neurotherapeutics 2021 Jan 6. Epub 2021 Jan 6.

Department of Pharmacology and Chemical Biology, Emory University, 1510 Clifton Road NE, Atlanta, GA, 30322, USA.

Prostaglandin-E (PGE), an important mediator of inflammation, achieves its functions via four different G protein-coupled receptors (EP1, EP2, EP3, and EP4). We previously demonstrated that the EP2 receptor plays a proinflammatory and neurodegenerative role after status epilepticus (SE). We recently developed TG8-260 as a second-generation highly potent and selective EP2 antagonist. Here, we investigate whether TG8-260 is anti-inflammatory and combats neuropathology caused by pilocarpine-induced SE in rats. Adult male Sprague-Dawley rats were injected subcutaneously with pilocarpine (380-400 mg/kg) to induce SE. Following 60 min of SE, the rats were administered three doses of TG8-260 or vehicle and were allowed to recover. Neurodegeneration, neuroinflammation, gliosis, and blood-brain barrier (BBB) integrity were examined 4 days after SE. The results confirmed that pilocarpine-induced SE results in hippocampal neurodegeneration and a robust inflammatory response that persists days after SE. Furthermore, inhibition of the EP2 receptor by TG8-260 administered beginning 2 h after SE significantly reduced hippocampal neuroinflammation and gliosis but, in distinction to the earlier generation EP2 antagonist, did not mitigate neuronal injury or BBB breakdown. Thus, attenuation of neuroinflammation and gliosis is a common feature of EP2 inhibition following SE.
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http://dx.doi.org/10.1007/s13311-020-00969-5DOI Listing
January 2021

Peripheral Myeloid Cell EP2 Activation Contributes to the Deleterious Consequences of Status Epilepticus.

J Neurosci 2021 02 8;41(5):1105-1117. Epub 2020 Dec 8.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia 30322.

A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2-mediated activation of prostaglandin EP2 receptors. The inflammatory response is typified by astrocytosis, microgliosis, erosion of the blood-brain barrier (BBB), formation of inflammatory cytokines, and brain infiltration of blood-borne monocytes. Our previous studies have shown that inhibition of monocyte brain invasion or systemic administration of an EP2 receptor antagonist relieves multiple deleterious consequences of SE. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and show that systemic EP2 antagonism blocks monocyte brain entry in male mice. The induction of hippocampal IL-6 after pilocarpine SE was nearly abolished in EP2 conditional KO mice. Serum albumin levels in the cortex, a measure of BBB breakdown, were significantly higher after SE in EP2-sufficient mice but not in EP2 conditional KOs. EP2 deficiency in innate immune cells accelerated the recovery from sickness behaviors following SE. Surprisingly, neurodegeneration was not alleviated in myeloid conditional KOs. Systemic EP2 antagonism prevented monocyte brain infiltration and provided broader rescue of SE-induced effects than myeloid EP2 ablation, including neuroprotection and broader suppression of inflammatory mediators. Reporter expression indicated that the cellular target of CD11b-driven Cre was circulating myeloid cells but, unexpectedly, not microglia. These findings indicate that activation of EP2 receptors on immune myeloid cells drives substantial deficits in behavior and disrupts the BBB after SE. The benefits of systemic EP2 antagonism can be attributed, in part, to blocking brain recruitment of blood-borne monocytes. Unabated seizures reduce quality of life, promote the development of epilepsy, and can be fatal. We previously identified activation of prostaglandin EP2 receptors as a driver of undesirable consequences of seizures. However, the relevant EP2-expressing cell types remain unclear. Here we identify peripheral innate immune cells as a driver of the EP2-related negative consequences of seizures. Removal of EP2 from peripheral immune cells was beneficial, abolishing production of a key inflammatory cytokine, accelerating weight regain, and limiting behavioral deficits. These findings provide evidence that EP2 engagement on peripheral immune and brain endothelia contributes to the deleterious effects of SE, and will assist in the development of beneficial therapies to enhance quality of life in individuals who suffer prolonged seizures.
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http://dx.doi.org/10.1523/JNEUROSCI.2040-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880294PMC
February 2021

Azaindole therapeutic agents.

Bioorg Med Chem 2020 12 30;28(24):115830. Epub 2020 Oct 30.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd, Atlanta, GA 30322, United States. Electronic address:

Azaindole structural framework is an integral part of several biologically active natural and synthetic organic molecules; and several FDA approved drugs for various diseases. In the last decade, quite a number of literature reports appeared describing the pharmacology, biological activity and therapeutic applications of a variety of azaindole molecules. This prompted the organic and medicinal chemistry community to develop novel synthetic methods for various azaindoles and test them for a bioactivity against a variety of biological targets. Herein, we have summarized the biological activity of therapeutically advanced clinical candidates and several preclinical candidate drugs that contain azaindole structural moiety.
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http://dx.doi.org/10.1016/j.bmc.2020.115830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736151PMC
December 2020

An Agonist Dependent Allosteric Antagonist of Prostaglandin EP2 Receptors.

ACS Chem Neurosci 2020 05 6;11(10):1436-1446. Epub 2020 May 6.

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, Georgia 30322, United States.

All reported prostaglandin EP2 receptor antagonists have a purely orthosteric, competitive mode of action. Herein, we report the characterization of compound (pubchem CID 664888) as the first EP2 antagonist that features a reversible, agonist dependent allosteric mode of action. Compound displayed an unsurmountable inhibition of cAMP accumulation stimulated by different EP2 agonists in C6 glioma cells overexpressing human EP2 (C6G-EP2). The degree of reduction of agonist potency and efficacy depended on the agonist employed. Negative allosteric modulation was not observed in C6G cells overexpressing human EP4, IP, or DP1 receptors. Moreover, in the murine microglial cell line that stably expresses human EP2 receptors (BV2-EP2), compound reduced the EP2 agonist-induced elevation of interleukin 6 (IL-6), IL-1β, and EP2 mRNA levels and increased that of tumor necrosis factor (TNF)-α. Compound was docked into a homology model of EP2. The predicted binding site on the cytoplasmic receptor surface was similar to that of allosteric inhibitors of the β2-adrenergic, CC chemokine receptor 9 (CCR9), and CC chemokine receptor 2 (CCR2) receptors, which supports the notion of a conserved G-protein-coupled receptor (GPCR) binding pocket for allosteric inhibitors. As the first agonist dependent negative allosteric modulator of EP2 receptor, the structure of this compound may provide a basis for developing improved allosteric modulators of EP2 receptors.
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http://dx.doi.org/10.1021/acschemneuro.0c00078DOI Listing
May 2020

Synthetic homoserine lactone analogues as antagonists of bacterial quorum sensing.

Bioorg Chem 2020 05 25;98:103698. Epub 2020 Feb 25.

Institute of Plant Biology and Biotechnology, Laboratory of Nanobiotechnology, University of Münster, Schlossgarten 3, D-48149 Münster, Germany; School of Food Science and Nutrition, University of Leeds, LS2 9JT Leeds, UK. Electronic address:

Quorum sensing (QS) is a density-dependent form of cell-cell communication that triggers the functional coordination of cooperative behaviors such as the production of virulence factors and biofilm formation. Quorum quenching (QQ) refers to all processes involved in the disruption of QS and is regarded as a promising strategy for treating bacterial infections. Herein, four compounds with closely related chemical structures to homoserine γ-lactone were synthesized and fully characterized. The compounds are termed TGK-series compounds. These compounds were subsequently tested in their QS inhibition activity using an E. coli Top 10 QS biosensor strain, a GFP QS reporter, that probes the capacity of bacteria to detect their cognate autoinducer N-(3-oxohexanoyl)-homoserine lactone (3OCHSL) substrate by means of a single intracellular protein LuxR. All TGK-series compounds were found to significantly inhibit the ability of bacteria to produce GFP but without exerting toxicity when applied at a concentration of 50 µM. In parallel, the interaction of TGK-series compounds with LuxR were studied by molecular docking simulations. These studies revealed that TGK-series compounds bound to the natural substrate N-(3-oxo-octanoyl)-l-homoserine lactone (OOHL) binding site and that the binding ability of the compounds with the TraR protein (a surrogate of LuxR) was even more favorable in comparison with the natural substrate. It was also uncovered that TGK-series compounds form stronger hydrophobic interactions with the TraR protein than 3OCHSL does, thus providing a rationale for the enhancement of the QQ activity of the synthetic TGK-series compounds. This study will serve to guide future works aimed to design promising novel QS inhibitor candidates on a rational basis.
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http://dx.doi.org/10.1016/j.bioorg.2020.103698DOI Listing
May 2020

Potent, Selective, Water Soluble, Brain-Permeable EP2 Receptor Antagonist for Use in Central Nervous System Disease Models.

J Med Chem 2020 02 16;63(3):1032-1050. Epub 2020 Jan 16.

Department of Pharmacology and Chemical Biology , Emory University School of Medicine , 1510 Clifton Rd , Atlanta , Georgia 30322 , United States.

Activation of prostanoid EP2 receptor exacerbates neuroinflammatory and neurodegenerative pathology in central nervous system diseases such as epilepsy, Alzheimer's disease, and cerebral aneurysms. A selective and brain-permeable EP2 antagonist will be useful to attenuate the inflammatory consequences of EP2 activation and to reduce the severity of these chronic diseases. We recently developed a brain-permeable EP2 antagonist (TG6-10-1), which displayed anti-inflammatory and neuroprotective actions in rodent models of status epilepticus. However, this compound exhibited moderate selectivity to EP2, a short plasma half-life in rodents (1.7 h) and low aqueous solubility (27 μM), limiting its use in animal models of chronic disease. With lead-optimization studies, we have developed several novel EP2 antagonists with improved water solubility, brain penetration, high EP2 potency, and selectivity. These novel inhibitors suppress inflammatory gene expression induced by EP2 receptor activation in a microglial cell line, reinforcing the use of EP2 antagonists as anti-inflammatory agents.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394479PMC
February 2020

Modulating neuroinflammation and oxidative stress to prevent epilepsy and improve outcomes after traumatic brain injury.

Neuropharmacology 2020 08 6;172:107907. Epub 2019 Dec 6.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd, Atlanta, GA, 30322, Georgia. Electronic address:

Traumatic brain injury (TBI) is a leading cause of death and disability in young adults worldwide. TBI survival is associated with persistent neuropsychiatric and neurological impairments, including posttraumatic epilepsy (PTE). To date, no pharmaceutical treatment has been found to prevent PTE or ameliorate neurological/neuropsychiatric deficits after TBI. Brain trauma results in immediate mechanical damage to brain cells and blood vessels that may never be fully restored given the limited regenerative capacity of brain tissue. This primary insult unleashes cascades of events, prominently including neuroinflammation and massive oxidative stress that evolve over time, expanding the brain injury, but also clearing cellular debris and establishing homeostasis in the region of damage. Accumulating evidence suggests that oxidative stress and neuroinflammatory sequelae of TBI contribute to posttraumatic epileptogenesis. This review will focus on possible roles of reactive oxygen species (ROS), their interactions with neuroinflammation in posttraumatic epileptogenesis, and emerging therapeutic strategies after TBI. We propose that inhibitors of the professional ROS-generating enzymes, the NADPH oxygenases and myeloperoxidase alone, or combined with selective inhibition of cyclooxygenase mediated signaling may have promise for the treatment or prevention of PTE and other sequelae of TBI. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274911PMC
August 2020

Novel Microglia Cell Line Expressing the Human EP2 Receptor.

ACS Chem Neurosci 2019 10 11;10(10):4280-4292. Epub 2019 Sep 11.

Department of Pharmacology and Chemical Biology , Emory University School of Medicine , Atlanta , Georgia 30322 , United States.

Recently, EP2 signaling pathways were shown to regulate the classical activation and death of microglia in rat primary microglial culture. The study of microglial cells has been challenging because they are time-consuming to isolate in culture, they are demanding in their growth requirements, and they have a limited lifespan. To circumvent these difficulties, we created a murine BV2 microglial cell line stably expressing human EP2 receptors (BV2-hEP2) and further explored EP2 modulation of microglial functions. The BV2-hEP2 cells displayed cAMP elevation when exposed to the selective EP2 receptor agonists (ONO-AE1-259-1 and CP544326), and this response was competitively inhibited by TG4-155, a selective EP2 antagonist (Schild = 2.6 nM). By contrast, untransfected BV2 cells were unresponsive to selective EP2 agonists. Similar to the case of rat primary microglia, BV2-hEP2 microglia treated with lipopolysaccharide (LPS) (100 ng/mL) displayed rapid and robust induction of the inflammatory mediators COX-2, IL-1β, TNFα, and IL-6. EP2 activation depressed TNFα induction but exacerbated that of the other inflammatory mediators. Like primary microglia, classically activated BV2 microglia phagocytose fluorescent-labeled latex microspheres. The presence of EP2, but not its activation by agonists, in BV2-hEP2 microglia reduced phagocytosis and proliferation by 65% and 32%, respectively, compared to BV2 microglia. Thus, BV2-hEP2 is the first microglial cell line that retains the EP2 modulation of immune regulation and phagocytic ability of native microglia. Suppression of phagocytosis by the EP2 protein appears unrelated to classical EP2 signaling pathways, which has implications for therapeutic development of EP2 antagonists.
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http://dx.doi.org/10.1021/acschemneuro.9b00311DOI Listing
October 2019

5xFAD Mice Display Sex-Dependent Inflammatory Gene Induction During the Prodromal Stage of Alzheimer's Disease.

J Alzheimers Dis 2019 ;70(4):1259-1274

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.

Alzheimer's disease (AD) pathology consists of extracellular deposits of amyloid-β peptides (Aβ) and intracellular neurofibrillary tangles. These pathological alterations are accompanied by a neuroinflammatory response consisting of increased expression of inflammatory mediators. An anti-inflammatory strategy designed to prevent or delay the development of AD would benefit from knowing when neuroinflammation appears in the transgenic models during prodromal disease stages relative to Aβ pathology. We investigated the expression patterns of inflammatory mediators in the brain of 5xFAD mice in comparison to development of Aβ deposition. Expression changes in inflammatory mediators and glial markers are more robust in female mice starting at three months of age, in contrast to males in which there is no clear trend through five months. Female and male 5xFAD mice also displayed an age-dependent increase in cortical Aβ deposition congruent with neuroinflammation. Thus, in the 5xFAD mouse model of AD, administration of an anti-inflammatory agent would be most efficacious when administered before three months of age.
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http://dx.doi.org/10.3233/JAD-180678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379326PMC
October 2020

A rat model of organophosphate-induced status epilepticus and the beneficial effects of EP2 receptor inhibition.

Neurobiol Dis 2020 01 25;133:104399. Epub 2019 Feb 25.

Department of Pharmacology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA.

This review describes an adult rat model of status epilepticus (SE) induced by diisopropyl fluorophosphate (DFP), and the beneficial outcomes of transient inhibition of the prostaglandin-E receptor EP2 with a small molecule antagonist, delayed by 2-4 h after SE onset. Administration of six doses of the selective EP2 antagonist TG6-10-1 over a 2-3 day period accelerates functional recovery, attenuates hippocampal neurodegeneration, neuroinflammation, gliosis and blood-brain barrier leakage, and prevents long-term cognitive deficits without blocking SE itself or altering acute seizure characteristics. This work has provided important information regarding organophosphate-induced seizure related pathologies in adults and revealed the effectiveness of delayed EP2 inhibition to combat these pathologies.
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http://dx.doi.org/10.1016/j.nbd.2019.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708729PMC
January 2020

The COX-2/prostanoid signaling cascades in seizure disorders.

Expert Opin Ther Targets 2019 01 2;23(1):1-13. Epub 2018 Dec 2.

a Department of Pharmacology , Emory University School of Medicine , Atlanta , GA , USA.

Introduction:A robust neuroinflammatory response is a prevalent feature of multiple neurological disorders, including epilepsy and acute status epilepticus. One component of this neuroinflammatory reaction is the induction of cyclooxygenase-2 (COX-2), synthesis of several prostaglandins and endocannabinoid metabolites, and subsequent activation of prostaglandin and related receptors. Neuroinflammation mediated by COX-2 and its downstream effectors has received considerable attention as a potential target class to ameliorate the deleterious consequences of neurological injury. Areas covered: Here we describe the roles of COX-2 as a major inflammatory mediator. In addition, we discuss the receptors for prostanoids PGE, prostaglandin D2, and PGF as potential therapeutic targets for inflammation-driven diseases. The consequences of prostanoid receptor activation after seizure activity are discussed with an emphasis on the utilization of small molecules to modulate prostanoid receptor activity. Expert opinion: Limited clinical trial experience is supportive but not definitive for a role of the COX signaling cascade in epileptogenesis. The cardiotoxicity associated with chronic coxib use, and the expectation that COX-2 inhibition will influence the levels of endocannabinoids, leukotrienes, and lipoxins as well as the prostaglandins and their endocannabinoid metabolite analogs, is shifting attention toward downstream synthases and receptors that mediate inflammation in the brain.
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http://dx.doi.org/10.1080/14728222.2019.1554056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481174PMC
January 2019

Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties.

Mol Pharm 2018 12 15;15(12):5809-5817. Epub 2018 Nov 15.

Department of Pharmacology, School of Medicine , Emory University , 1510 Clifton Rd , Atlanta , Georgia 30322 , United States.

The prostaglandin E receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However, earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life, and low aqueous solubility, which renders them suboptimal for testing in animal models of disease. We now report a novel compound TG8-69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti-inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases, including rheumatoid arthritis, endometriosis, and cancer, in which EP2 appears to play a pathogenic role.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633905PMC
December 2018

Discovery of 2-Piperidinyl Phenyl Benzamides and Trisubstituted Pyrimidines as Positive Allosteric Modulators of the Prostaglandin Receptor EP2.

ACS Chem Neurosci 2018 04 4;9(4):699-707. Epub 2018 Jan 4.

Department of Pharmacology, School of Medicine , Emory University , Atlanta , Georgia 30322 , United States.

Prostaglandin E2 (PGE) via its Gα-coupled EP2 receptor protects cerebral cortical neurons from excitotoxic and anoxic injury, though EP2 receptor activation can also cause secondary neurotoxicity in chronic inflammation. We performed a high-throughput screen of a library of 292 000 small molecules and identified several compounds that have a 2-piperidinyl phenyl benzamide or trisubstituted pyrimidine core as positive modulators for human EP2 receptor. The most active compounds increased the potency of PGE on EP2 receptor 4-5-fold at 20 μM without altering efficacy, indicative of an allosteric mechanism. These compounds did not augment the activity of the other Gα-coupled PGE receptor subtype EP4 and showed neuroprotection against N-methyl-d-aspartate (NMDA)-induced excitotoxicity. These newly developed compounds represent second-generation allosteric potentiators for EP2 receptor and shed light on a promising neuroprotective strategy. They should prove valuable as molecular tools to achieve a better understanding of the dichotomous action of brain EP2 receptor activation.
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http://dx.doi.org/10.1021/acschemneuro.7b00486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318807PMC
April 2018

Prostaglandin dehydrogenase is a target for successful induction of cervical ripening.

Proc Natl Acad Sci U S A 2017 08 17;114(31):E6427-E6436. Epub 2017 Jul 17.

The Cecil H. and Ida Green Center for Reproductive Biology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

The cervix represents a formidable structural barrier for successful induction of labor. Approximately 10% of pregnancies undergo induction of cervical ripening and labor with prostaglandin (PG) E or PGE analogs, often requiring many hours of hospitalization and monitoring. On the other hand, preterm cervical ripening in the second trimester predicts preterm birth. The regulatory mechanisms of this paradoxical function of the cervix are unknown. Here, we show that PGE uses cell-specific EP2 receptor-mediated increases in Ca to dephosphorylate and translocate histone deacetylase 4 (HDAC4) to the nucleus for repression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH). The crucial role of 15-PGDH in cervical ripening was confirmed in vivo. Although PGE or 15-PGDH inhibitor alone did not alter gestational length, treatment with 15-PGDH inhibitor + PGE or metabolism-resistant dimethyl-PGE resulted in preterm cervical ripening and delivery in mice. The ability of PGE to selectively autoamplify its own synthesis in stromal cells by signaling transcriptional repression of elucidates long sought-after molecular mechanisms that govern PG action in the cervix. This report details unique mechanisms of action in the cervix and serves as a catalyst for () the use of 15-PGDH inhibitors to initiate or amplify low-dose PGE-mediated cervical ripening or () EP2 receptor antagonists, HDAC4 inhibitors, and 15-PGDH activators to prevent preterm cervical ripening and preterm birth.
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http://dx.doi.org/10.1073/pnas.1704945114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547630PMC
August 2017

Ethylatropine Bromide as a Peripherally Restricted Muscarinic Antagonist.

ACS Chem Neurosci 2017 04 6;8(4):712-717. Epub 2017 Jan 6.

Department of Pharmacology, Emory University , 1510 Clifton Road NE, Atlanta, Georgia 30322, United States.

Quaternary ammonium analogues of atropine that are unable to cross the blood-brain barrier are used to alleviate peripheral muscarinic toxicity in animal models of epilepsy produced by systemic administration of pilocarpine or diisopropylfluorophosphate (DFP). Currently, methylatropine is the most popular and potent of these quaternary derivatives; however, it is expensive and produced in limited quantity. Here, we propose the use of ethylatropine bromide as an alternative to methylatropine. The synthesis of ethylatropine bromide is simple, inexpensive and has low environmental impact. We demonstrate the efficacy of ethylatropine bromide to antagonize the carbachol induced rise in intracellular calcium in a calcium mobilization assay, and its ability to prevent pilocarpine-induced total fluid secretions in mice without blocking pilocarpine-induced seizures. The ease of synthesis, cost effectiveness, and efficacy makes ethylatropine bromide a desirable alternative to methylatropine as a peripherally restricted acetylcholine receptor antagonist.
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http://dx.doi.org/10.1021/acschemneuro.6b00334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872150PMC
April 2017

Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats.

Neuropharmacology 2016 11 29;110(Pt A):419-430. Epub 2016 Jul 29.

Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA.

Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6-12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP.
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http://dx.doi.org/10.1016/j.neuropharm.2016.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028311PMC
November 2016

Thioxo-dihydroquinazolin-one Compounds as Novel Inhibitors of Myeloperoxidase.

ACS Med Chem Lett 2015 Oct 31;6(10):1047-52. Epub 2015 Aug 31.

Department of Pathology and Laboratory Medicine, Emory University , Atlanta, Georgia 30322, United States.

Myeloperoxidase (MPO) is a key antimicrobial enzyme, playing a normal role in host defense, but also contributing to inflammatory conditions including neuroinflammatory diseases such as Parkinson's and Alzheimer's. We synthesized and characterized more than 50 quinazolin-4(1H)-one derivatives and showed that this class of compounds inhibits MPO with IC50 values as low as 100 nM. Representative compounds showed partially reversible inhibition that was competitive with respect to Amplex Red substrate and did not result in the accumulation of MPO Compound II. Members of this group show promise for therapeutic development for the treatment of diseases in which inflammation plays a pathogenic role.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601060PMC
October 2015

Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells.

Clin Epigenetics 2015 21;7:84. Epub 2015 Aug 21.

Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London, Hammersmith Hospital Campus, London, W12 ONN UK ; Section of Molecular Pathology, Institute of Cancer Research, Sutton, SM2 5NG UK.

Background: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks.

Results: We report that gene expression and inhibition of triple negative breast cancer cell growth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2, either by siRNA knockdown or pharmacological inhibition, rather than either enzyme independently. Indeed, expression of certain genes is only induced upon dual inhibition. We sought to identify compounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-based assay, based on the substrate competitive EHMT2 inhibitor BIX01294, we have identified proof-of-concept compounds that induce re-expression of a subset of genes consistent with dual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marks and an increase in permissive marks at the promoter and transcription start site of re-expressed genes, while Western analysis showed reduction in global levels of H3K27me3 and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma cell lines with low to sub-micromolar IC50s. Biochemically, the compounds are substrate competitive inhibitors against both EZH2 and EHMT1/2.

Conclusions: We have demonstrated that dual inhibition of EZH2 and EHMT2 is more effective at eliciting biological responses of gene transcription and cancer cell growth inhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells.
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http://dx.doi.org/10.1186/s13148-015-0118-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545913PMC
August 2015

Evaluation of WO 2012/177618 A1 and US-2014/0179750 A1: novel small molecule antagonists of prostaglandin-E2 receptor EP2.

Authors:
Thota Ganesh

Expert Opin Ther Pat 2015 Jul 15;25(7):837-44. Epub 2015 Mar 15.

Emory University School of Medicine, Department of Pharmacology , 1510 Clifton Rd, Atlanta, GA 30322 , USA +1 404 727 7393 ; +1 404 727 0365 ;

Recent studies underscore that prostaglandin-E2 exerts mostly proinflammatory effects in chronic CNS and peripheral disease models, mainly through a specific prostanoid receptor EP2. However, very few highly characterized EP2 receptor antagonists have been reported until recently, when Pfizer and Emory University published two distinct classes of EP2 antagonists with good potency, selectivity and pharmacokinetics. The purpose of this article is to evaluate recently published patents WO 2012/177618 A1 and US-2014/0179750 A1 from Emory, which describe a number of cinnamic amide- and amide-derivatives as a potent antagonists of EP2 receptor, and their neuroprotective effects in in vitro and in an in vivo model. A selected compound from this patent(s) also attenuates prostate cancer cell growth and invasion in vitro, suggesting these compounds should be developed for therapeutic use.
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http://dx.doi.org/10.1517/13543776.2015.1025752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844339PMC
July 2015

Context-dependent GluN2B-selective inhibitors of NMDA receptor function are neuroprotective with minimal side effects.

Neuron 2015 Mar 26;85(6):1305-1318. Epub 2015 Feb 26.

Department of Pharmacology, Emory University, Atlanta, GA 30322 USA.

Stroke remains a significant problem despite decades of work on neuroprotective strategies. NMDA receptor (NMDAR) antagonists are neuroprotective in preclinical models, but have been clinically unsuccessful, in part due to side effects. Here we describe a prototypical GluN2B-selective antagonist with an IC50 value that is 10-fold more potent at acidic pH 6.9 associated with ischemic tissue compared to pH 7.6, a value close to the pH in healthy brain tissue. This should maximize neuroprotection in ischemic tissue while minimizing on-target side effects associated with NMDAR blockade in noninjured brain regions. We have determined the mechanism underlying pH-dependent inhibition and demonstrate the utility of this approach in vivo. We also identify dicarboxylate dimers as a novel proton sensor in proteins. These results provide insight into the molecular basis of pH-dependent neuroprotective NMDAR block, which could be beneficial in a wide range of neurological insults associated with tissue acidification.
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http://dx.doi.org/10.1016/j.neuron.2015.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368485PMC
March 2015

EP2 Receptor Signaling Regulates Microglia Death.

Mol Pharmacol 2015 Jul 25;88(1):161-70. Epub 2015 Feb 25.

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (Y.F., M.-S.Y., J.J., T.G., R.D.); Neurology Department, Xiangya Hospital, Hunan, China (Y.F.); and Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea (M.-S.Y., E.J.).

The timely resolution of inflammation prevents continued tissue damage after an initial insult. In the brain, the death of activated microglia by apoptosis has been proposed as one mechanism to resolve brain inflammation. How microglial death is regulated after activation is still unclear. We reported that exposure to lipopolysaccharide (LPS) and interleukin (IL)-13 together initially activates and then kills rat microglia in culture by a mechanism dependent on cyclooxygenase-2 (COX-2). We show here that activation of the E prostanoid receptor 2 (EP2, PTGER2) for prostaglandin E2 mediates microglial death induced by LPS/IL-13, and that EP2 activation by agonist alone kills microglia. Both EP2 antagonists and reactive oxygen scavengers block microglial death induced by either LPS/IL-13 or EP2 activation. By contrast, the homeostatic induction of heme oxygenase 1 (Hmox1) by LPS/IL-13 or EP2 activation protects microglia. Both the Hmox1 inducer cobalt protoporphyrin and a compound that releases the Hmox1 product carbon monoxide (CO) attenuated microglial death produced by LPS/IL-13. Whereas CO reduced COX-2 protein expression, EP2 activation increased Hmox1 and COX-2 expression at both the mRNA and protein level. Interestingly, caspase-1 inhibition prevented microglial death induced by either LPS/IL-13 or low (but not high) concentrations of butaprost, suggestive of a predominantly pyroptotic mode of death. Butaprost also caused the expression of activated caspase-3 in microglia, pointing to apoptosis. These results indicate that EP2 activation, which initially promotes microglial activation, later causes delayed death of activated microglia, potentially contributing to the resolution phase of neuroinflammation.
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http://dx.doi.org/10.1124/mol.115.098202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468645PMC
July 2015

Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus.

Neuropharmacology 2015 Jun 3;93:15-27. Epub 2015 Feb 3.

Department of Pharmacology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA.

Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague-Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80-150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats.
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http://dx.doi.org/10.1016/j.neuropharm.2015.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387070PMC
June 2015

Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus.

Neurobiol Dis 2015 Apr 17;76:126-136. Epub 2015 Jan 17.

Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, United States.

As a prominent inflammatory effector of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) mediates brain inflammation and injury in many chronic central nervous system (CNS) conditions including seizures and epilepsy, largely through its receptor subtype EP2. However, EP2 receptor activation might also be neuroprotective in models of excitotoxicity and ischemia. These seemingly incongruent observations expose the delicacy of immune and inflammatory signaling in the brain; thus the therapeutic window for quelling neuroinflammation might vary with injury type and target molecule. Here, we identify a therapeutic window for EP2 antagonism to reduce delayed mortality and functional morbidity after status epilepticus (SE) in mice. Importantly, treatment must be delayed relative to SE onset to be effective, a finding that could be explained by the time-course of COX-2 induction after SE and compound pharmacokinetics. A large number of inflammatory mediators were upregulated in hippocampus after SE with COX-2 and IL-1β temporally leading many others. Thus, EP2 antagonism represents a novel anti-inflammatory strategy to treat SE with a tightly-regulated therapeutic window.
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http://dx.doi.org/10.1016/j.nbd.2014.12.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408774PMC
April 2015

Development of second generation EP2 antagonists with high selectivity.

Eur J Med Chem 2014 Jul 3;82:521-35. Epub 2014 Jun 3.

Department of Pharmacology, School of Medicine, Emory University, 1510 Clifton Rd, Atlanta, GA 30322, USA.

EP2 receptor has emerged as an important biological target for therapeutic intervention. In particular, it has been shown to exacerbate disease progression of a variety of CNS and peripheral diseases. Deletion of the EP2 receptor in mouse models recapitulates several features of the COX-2 inhibition, thus presenting a new avenue for anti-inflammatory therapy which could bypass some of the adverse side effects observed by the COX-2 inhibition therapy. We have recently reported a cinnamic amide class of EP2 antagonists with high potency, but these compounds exhibited a moderate selectivity against prostanoid receptor DP1. Moreover they possess acrylamide moiety in the structure, which may result in liver toxicity over longer period of use in a chronic disease model. Thus, we now developed a second generation compounds that devoid of the acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other prostanoid receptors.
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http://dx.doi.org/10.1016/j.ejmech.2014.05.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108197PMC
July 2014

Lead optimization studies of cinnamic amide EP2 antagonists.

J Med Chem 2014 May 5;57(10):4173-84. Epub 2014 May 5.

Department of Pharmacology, School of Medicine, Emory University , 1510 Clifton Road, Atlanta, Georgia 30322, United States.

Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role.
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http://dx.doi.org/10.1021/jm5000672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032197PMC
May 2014

High-throughput assays for superoxide and hydrogen peroxide: design of a screening workflow to identify inhibitors of NADPH oxidases.

J Biol Chem 2014 Jun 24;289(23):16176-89. Epub 2014 Apr 24.

From the Department of Biophysics and Free Radical Research Center and

Recent progress characterizing the reaction mechanism(s) of fluorescent probes with reactive oxygen species has made it possible to rigorously analyze these reactive species in biological systems. We have developed rapid high throughput-compatible assays for monitoring cellular production of superoxide radical anion and hydrogen peroxide using hydropropidine and coumarin boronic acid probes, respectively. Coupling plate reader-based fluorescence measurements with HPLC-based simultaneous monitoring of superoxide radical anion and hydrogen peroxide provides the basis for the screening protocol for NADPH oxidase (Nox) inhibitors. Using this newly developed approach along with the medium-throughput plate reader-based oximetry and EPR spin trapping as confirmatory assays, it is now eminently feasible to rapidly and reliably identify Nox enzyme inhibitors with a markedly lower rate of false positives. These methodological advances provide an opportunity to discover selective inhibitors of Nox isozymes, through enhanced conceptual understanding of their basic mechanisms of action.
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http://dx.doi.org/10.1074/jbc.M114.548693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047388PMC
June 2014

Cyclooxygenase-2 in epilepsy.

Epilepsia 2014 Jan 8;55(1):17-25. Epub 2013 Nov 8.

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, U.S.A.

Epilepsy is one of the more prevalent neurologic disorders in the world, affecting approximately 50 million people of different ages and backgrounds. Epileptic seizures propagating through both lobes of the forebrain can have permanent debilitating effects on a patient's cognitive and somatosensory brain functions. Epilepsy, defined by the sporadic occurrence of spontaneous recurrent seizures (SRS), is often accompanied by inflammation of the brain. Pronounced increases in the expression of key inflammatory mediators (e.g., interleukin -1β [IL-1β], tumor necrosis factor alpha [TNFα], cyclooxygenase-2 [COX-2], and C-X-C motif chemokine 10 [CXCL10]) after seizures may cause secondary damage in the brain and increase the likelihood of repetitive seizures. The COX-2 enzyme is induced rapidly during seizures. The increased level of COX-2 in specific areas of the epileptic brain can help to identify regions of seizure-induced brain inflammation. A good deal of effort has been expended to determine whether COX-2 inhibition might be neuroprotective and represent an adjunct therapeutic strategy along with antiepileptic drugs used to treat epilepsy. However, the effectiveness of COX-2 inhibitors on epilepsy animal models appears to depend on the timing of administration. With all of the effort placed on making use of COX-2 inhibitors as therapeutic agents for the treatment of epilepsy, inflammation, and neurodegenerative diseases there has yet to be a selective and potent COX-2 inhibitor that has shown a clear therapeutic outcome with acceptable side effects.
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http://dx.doi.org/10.1111/epi.12461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956447PMC
January 2014

Synthesis of isotopically labeled epothilones.

J Labelled Comp Radiopharm 2014 Feb 5;57(2):78-81. Epub 2013 Dec 5.

Department of Chemistry and Virginia Tech Center for Drug Discovery, M/C 0212, Virginia Tech, Blacksburg, VA, 24061, USA.

The epothilones, including epothilones B and D, are macrocyclic lactones, which have potent cytotoxicities and promote the polymerization of tubulin to mictotubules by binding to and stabilizing the tubulin polymer. They have a very similar mechanism of action to paclitaxel (Taxol®). The determination of the microtubule-binding conformation of the epothilones is an important piece of information in designing improved analogs for possible clinical use, and internuclear distance information that will assist the determination of this conformation can be obtained by rotational echo double resonance (REDOR) NMR studies of microtubule-bound epothilones with appropriate stable isotope labels. Analogs of epothilone B and epothilone D with [(2) H3 ] and [(19) F] labels were prepared from an advanced precursor for potential use in REDOR NMR studies to determine internuclear distances in tubulin-bound ligand.
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http://dx.doi.org/10.1002/jlcr.3144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979290PMC
February 2014

Prostanoid receptor EP2 as a therapeutic target.

Authors:
Thota Ganesh

J Med Chem 2014 Jun 4;57(11):4454-65. Epub 2013 Dec 4.

Department of Pharmacology, Emory University School of Medicine , 1510 Clifton Road, Atlanta, Georgia, 30322, United States.

Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.
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http://dx.doi.org/10.1021/jm401431xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045661PMC
June 2014

Discovery and characterization of carbamothioylacrylamides as EP selective antagonists.

ACS Med Chem Lett 2013 Jul;4(7):616-621

Department of Pharmacology, School of Medicine, Emory University, Atlanta, Georgia 30322, United States.

Prostanoid receptor EP2 is emerging as a novel target for development of anti-inflammatory drugs for the treatment of chronic neurodegenerative and peripheral diseases; however, the availability of EP2 antagonist probes for exploration of peripheral disease models is very limited. We now report identification and characterization of a novel chemical class of compounds that show nanomolar potency and competitive antagonism of the EP2 receptor. A compound in this class, TG6-129, showed prolonged plasma half-life and did not cross the blood brain barrier. This compound also suppressed the induction of inflammatory mRNA markers in a macrophage cell line upon activation of EP2. Thus, this compound could be useful as a probe for a variety of peripheral chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease, in which EP2 appears to play a pathogenic role.
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http://dx.doi.org/10.1021/ml400112hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731160PMC
July 2013