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Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Tian J, Teuscher KB, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey RJ, Tansey WP, Stauffer SR, Lee T, Fesik SW
(2020) J Med Chem 63: 656-675
MeSH Terms: Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Chromatin, Crystallography, X-Ray, Drug Design, Drug Discovery, Epigenetic Repression, Genes, myc, Humans, Intracellular Signaling Peptides and Proteins, Quinolones, Structure-Activity Relationship, WD40 Repeats
Show Abstract · Added March 3, 2020
WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.
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16 MeSH Terms
Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy.
West JD, Galindo CL, Kim K, Shin JJ, Atkinson JB, Macias-Perez I, Pavliv L, Knollmann BC, Soslow JH, Markham LW, Carrier EJ
(2019) J Am Heart Assoc 8: e011902
MeSH Terms: Animals, Bridged Bicyclo Compounds, Heterocyclic, Cardiomyopathies, Disease Models, Animal, Female, Male, Mice, Mice, Inbred mdx, Mice, Knockout, Muscular Dystrophy, Duchenne, Oxazoles, Prostaglandin Antagonists, Random Allocation, Receptors, Thromboxane
Show Abstract · Added March 4, 2020
Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/mTR double knockout, and delta-sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TPr antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta-sarcoglycan knockout mice, respectively. TPr antagonism improved cardiac output in mdx/utrn double knockout and mdx/mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta-sarcoglycan knockout mice. Cardiac fibrosis in delta-sarcoglycan knockout was reduced with TPr antagonism, which also normalized cardiac expression of claudin-5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TPr antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb-girdle MD. Based on these studies, ifetroban and other TPr antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD.
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14 MeSH Terms
Intraarterial administration of norcantharidin attenuates ischemic stroke damage in rodents when given at the time of reperfusion: novel uses of endovascular capabilities.
Khan IS, Odom M, Ehtesham M, Colvin D, Quarles CC, McLaughlin B, Singer RJ
(2016) J Neurosurg 125: 152-9
MeSH Terms: Animals, Brain Ischemia, Bridged Bicyclo Compounds, Heterocyclic, Disease Models, Animal, Injections, Intra-Arterial, Male, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Rats, Stroke
Show Abstract · Added April 25, 2016
OBJECT Matrix metalloprotease-9 (MMP-9) plays a critical role in infarct progression, blood-brain barrier (BBB) disruption, and vasogenic edema. While systemic administration of MMP-9 inhibitors has shown neuroprotective promise in ischemic stroke, there has been little effort to incorporate these drugs into endovascular modalities. By modifying the rodent middle cerebral artery occlusion (MCAO) model to allow local intraarterial delivery of drugs, one has the ability to mimic endovascular delivery of therapeutics. Using this model, the authors sought to maximize the protective potential of MMP-9 inhibition by intraarterial administration of an MMP-9 inhibitor, norcantharidin (NCTD). METHODS Spontaneously hypertensive rats were subjected to 90-minute MCAO followed immediately by local intraarterial administration of NCTD. The rats' neurobehavioral performances were scored according to the ladder rung walking test results and the Garcia neurological test for as long as 7 days after stroke. MRI was also conducted 24 hours after the stroke to assess infarct volume and BBB disruption. At the end of the experimental protocol, rat brains were used for active MMP-9 immunohistochemical analysis to assess the degree of MMP-9 inhibition. RESULTS NCTD-treated rats showed significantly better neurobehavioral scores for all days tested. MR images also depicted significantly decreased infarct volumes and BBB disruption 24 hours after stroke. Inhibition of MMP-9 expression in the ischemic region was depicted on immunohistochemical analysis, wherein treated rats showed decreased active MMP-9 staining compared with controls. CONCLUSIONS Intraarterial NCTD significantly improved outcome when administered at the time of reperfusion in a spontaneously hypertensive rat stroke model. This study suggests that supplementing endovascular revascularization with local neuroprotective drug therapy may be a viable therapeutic strategy.
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10 MeSH Terms
Multitargeting of selected prostanoid receptors provides agents with enhanced anti-inflammatory activity in macrophages.
Wang JW, Woodward DF, Martos JL, Cornell CL, Carling RW, Kingsley PJ, Marnett LJ
(2016) FASEB J 30: 394-404
MeSH Terms: Anti-Inflammatory Agents, Non-Steroidal, Bridged Bicyclo Compounds, Heterocyclic, Cells, Cultured, Cinnamates, Humans, Macrophages, Receptors, Prostaglandin, Receptors, Thromboxane, Substrate Specificity
Show Abstract · Added February 22, 2016
A polypharmacologic approach to prostanoid based anti-inflammatory therapeutics was undertaken in order to exploit both the anti- and proinflammatory properties attributed to the various prostanoid receptors. Multitargeting of selected prostanoid receptors yielded a prototype compound, compound 1 (AGN 211377), that antagonizes prostaglandin D2 receptors (DPs) DP1 (49) and DP2 (558), prostaglandin E2 receptors (EPs) EP1 (266) and EP4 (117), prostaglandin F2α receptor (FP) (61), and thromboxane A2 receptor (TP) (11) while sparing EP2, EP3, and prostaglandin I2 receptors (IPs); Kb values (in nanomoles) are given in parentheses. Compound 1 evoked a pronounced inhibition of cytokine/chemokine secretion from lipopolysaccharide or TNF-α stimulated primary human macrophages. These cytokine/chemokines included cluster of designation 40 receptor (CD40), epithelial-derived neutrophil-activating protein 78 (ENA-78), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), IL-8, IL-18, monocyte chemotactic protein-1 (CCL2) (MCP-1), tissue plasminogen activator inhibitor (PAI-1), and regulated on activation, normal T cell expressed and secreted (RANTES). In contrast, the inhibitory effects of most antagonists selective for a single receptor were modest or absent, and selective EP2 receptor blockade increased cytokine release in some instances. Compound 1 also showed clear superiority to the cyclooxygenase inhibitors diclofenac and rofecoxib. These findings reveal that blockade of multiple prostanoid receptors, with absent antagonism of EP2 and IP, may provide more effective anti-inflammatory activity than global suppression of prostanoid synthesis or highly selective prostanoid receptor blockade. These investigations demonstrate the first working example of prostanoid receptor polypharmacology for potentially safer and more effective anti-inflammatory therapeutics by blocking multiple proinflammatory receptors while sparing those with anti-inflammatory activity.
© FASEB.
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9 MeSH Terms
A randomized, double-blind, placebo-controlled crossover study of α4β 2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder.
Jucaite A, Öhd J, Potter AS, Jaeger J, Karlsson P, Hannesdottir K, Boström E, Newhouse PA, Paulsson B
(2014) Psychopharmacology (Berl) 231: 1251-65
MeSH Terms: Adult, Attention Deficit Disorder with Hyperactivity, Bridged Bicyclo Compounds, Heterocyclic, Cognition, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Nicotinic Agonists, Psychiatric Status Rating Scales, Receptors, Nicotinic, Time Factors, Tobacco Use Disorder, Treatment Outcome, Young Adult
Show Abstract · Added March 3, 2020
RATIONALE - Stimulation of nicotinic cholinergic systems has been shown to alleviate ADHD symptoms and to improve cognitive performance. AZD1446 is a selective α4β2* nicotinic acetylcholine receptor agonist with potential effect on the symptoms of ADHD.
OBJECTIVES - The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AZD1446 in adults with ADHD treated for 2 weeks.
METHOD - This was a randomized, double-blind, placebo-controlled crossover trial. Participants were 79 adults with ADHD, grouped according to their use of nicotine-containing products. Nicotine non-users received placebo and two of three AZD1446 treatment regimens (80 mg tid, 80 mg qd, 10 mg tid). Nicotine users received placebo, AZD1446 80 mg tid and 80 mg qd. Efficacy measures included the Conners' Adult ADHD Rating Scale and cognitive measures of immediate and delayed verbal episodic memory, learning, attention, working memory, executive functioning, and spatial problem solving (CogState computerized test battery).
RESULTS - There was no significant effect of AZD1446 on any of the clinical scores irrespective of dose, schedule, or concomitant use of nicotine products. A statistically significant improvement was seen on the Groton Maze Learning Task, a measure of executive functioning, in nicotine non-users after treatment with AZD1446 80 mg qd.
CONCLUSIONS - AZD1446 was well tolerated, but did not significantly improve ADHD symptoms after 2 weeks of treatment compared to placebo. While the present study does not support the therapeutic utility of AZD1446 in ADHD, its potential pro-cognitive effects remain to be explored in other neuropsychiatric disorders.
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MeSH Terms
Isoprostanes as physiological mediators of transition to newborn life: novel mechanisms regulating patency of the term and preterm ductus arteriosus.
Chen JX, O'Mara PW, Poole SD, Brown N, Ehinger NJ, Slaughter JC, Paria BC, Aschner JL, Reese J
(2012) Pediatr Res 72: 122-8
MeSH Terms: Analysis of Variance, Animals, Animals, Newborn, Bridged Bicyclo Compounds, Heterocyclic, Dinoprost, Dinoprostone, Ductus Arteriosus, Ductus Arteriosus, Patent, Fatty Acids, Unsaturated, Female, Gas Chromatography-Mass Spectrometry, Gene Expression Profiling, Hydrazines, Isoprostanes, Mice, Myography, Oxidative Stress, Oxygen, Pregnancy, Premature Birth, Receptors, Prostaglandin E, EP4 Subtype, Receptors, Thromboxane A2, Prostaglandin H2, Vasodilation
Show Abstract · Added May 26, 2015
BACKGROUND - Increased oxygen tension at birth regulates physiologic events that are essential to postnatal survival, but the accompanying oxidative stress may also generate isoprostanes. We hypothesized that isoprostanes regulate ductus arteriosus (DA) function during postnatal vascular transition.
METHODS - Isoprostanes were measured by gas chromatography-mass spectrometry. DA tone was assessed by pressure myography. Gene expression was measured by quantitative PCR.
RESULTS - Oxygen exposure was associated with increased 8-iso-prostaglandin (PG)F2α in newborn mouse lungs. Both 8-iso-PGE2 and 8-iso-PGF2α induced concentration-dependent constriction of the isolated term DA, which was reversed by the thromboxane A2 (TxA2) receptor antagonist SQ29548. SQ29548 pretreatment unmasked an isoprostane-induced DA dilation mediated by the EP4 PG receptor. Exposure of the preterm DA to 8-iso-PGE2 caused unexpected DA relaxation that was reversed by EP4 antagonism. In contrast, exposure to 8-iso-PGF2α caused preterm DA constriction via TxA2 receptor activation. Further investigation revealed the predominance of the TxA2 receptor at term, whereas the EP4 receptor was expressed and functionally active from mid-gestation onward.
CONCLUSION - This study identifies a novel physiological role for isoprostanes during postnatal vascular transition and provide evidence that oxidative stress may act on membrane lipids to produce vasoactive mediators that stimulate physiological DA closure at birth or induce pathological patency of the preterm DA.
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23 MeSH Terms
Pyridoxine-derived bicyclic aminopyridinol antioxidants: synthesis and their antioxidant activities.
Nam TG, Ku JM, Rector CL, Choi H, Porter NA, Jeong BS
(2011) Org Biomol Chem 9: 8475-82
MeSH Terms: Aminopyridines, Antioxidants, Bridged Bicyclo Compounds, Heterocyclic, Molecular Structure, Pyridoxine
Show Abstract · Added March 7, 2014
A few facile synthetic pathways for bicyclic aminopyridinol antioxidants are presented. Attachment of a long alkyl chain to the bicyclic pyridinol scaffold was established using ester linkage. Non-substituted pyrrolopyridinols and 1,3-oxazine-fused pyridinols were also synthesized as novel antioxidant scaffolds. Antioxidant activities were measured by a radical clock method and new compounds prepared are comparable to the best bicyclic aminopyridinol antioxidants.
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5 MeSH Terms
Cytoskeleton disruption in J774 macrophages: consequences for lipid droplet formation and cholesterol flux.
Weibel GL, Joshi MR, Jerome WG, Bates SR, Yu KJ, Phillips MC, Rothblat GH
(2012) Biochim Biophys Acta 1821: 464-72
MeSH Terms: Actin Cytoskeleton, Animals, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Cholesterol Esters, Cytochalasin D, Cytoskeletal Proteins, Foam Cells, Hydrolysis, Lipid Metabolism, Mice, Organelle Size, Organelles, Proteome, Sterol Esterase, Thiazolidines, Triglycerides
Show Abstract · Added December 10, 2013
Macrophages store excess unesterified cholesterol (free, FC) in the form of cholesteryl ester (CE) in cytoplasmic lipid droplets. The hydrolysis of droplet-CE in peripheral foam cells is critical to HDL-promoted reverse cholesterol transport because it represents the first step in cellular cholesterol clearance, as only FC is effluxed from cells to HDL. Cytoplasmic lipid droplets move within the cell utilizing the cytoskeletal network, but, little is known about the influence of the cytoskeleton on lipid droplet formation. To understand this role we employed cytochalasin D (cyt.D) to promote actin depolymerization in J774 macrophages. Incubating J774 with acetylated LDL creates foam cells having a 4-fold increase in cellular cholesterol content (30-40% cholesterol present as cholesteryl ester (CE)) in cytoplasmic droplets. Lipid droplets formed in the presence of cyt.D are smaller in diameter. CE-deposition and -hydrolysis are decreased when cells are cholesterol-enriched in the presence of cyt.D or latrunculin A, another cytoskeleton disrupting agent. However, when lipid droplets formed in the presence of cyt.D are isolated and incubated with an exogenous CE hydrolase, the CE is more rapidly metabolized compared to droplets from control cells. This is apparently due to the smaller size and altered lipid composition of the droplets formed in the presence of cyt.D. Cytoskeletal proteins found on CE droplets influence droplet lipid composition and maturation in model foam cells. In J774 macrophages, cytoskeletal proteins are apparently involved in facilitating the interaction of lipid droplets and a cytosolic neutral CE hydrolase and may play a role in foam cell formation. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
Copyright © 2011 Elsevier B.V. All rights reserved.
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17 MeSH Terms
Activation of group II metabotropic glutamate receptors induces long-term depression of excitatory synaptic transmission in the substantia nigra pars reticulata.
Johnson KA, Niswender CM, Conn PJ, Xiang Z
(2011) Neurosci Lett 504: 102-106
MeSH Terms: Amino Acids, Animals, Basal Ganglia, Bridged Bicyclo Compounds, Heterocyclic, Data Interpretation, Statistical, Dose-Response Relationship, Drug, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Mice, Mice, Knockout, Neuronal Plasticity, Patch-Clamp Techniques, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Substantia Nigra, Synaptic Transmission, Xanthenes, gamma-Aminobutyric Acid
Show Abstract · Added February 19, 2015
Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) has been implicated as a potential therapeutic strategy for treating both motor symptoms and progressive neurodegeneration in Parkinson's disease (PD). Modulation of excitatory transmission in the basal ganglia represents a possible mechanism by which group II mGlu agonists could exert antiparkinsonian effects. Previous studies have identified reversible effects of mGlu2/3 activation on excitatory transmission at various synapses in the basal ganglia, including the excitatory synapse between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). Using whole-cell patch clamp studies of GABAergic SNr neurons in rat midbrain slices, we have found that a prolonged activation of group II mGlus by the selective agonist LY379268 induces a long-term depression (LTD) of evoked excitatory postsynaptic current (EPSC) amplitude. Bath application of LY379268 (100nM, 10min) induced a marked reduction in EPSC amplitude, and excitatory transmission remained depressed for at least 40min after agonist washout. The effect of LY379268 was concentration-dependent and was completely blocked by the group II mGlu-preferring antagonist LY341495 (500nM). To determine the relative contributions of mGlu2 and mGlu3 to the LTD induced by LY379268, we tested the ability of LY379268 (100nM) to induce LTD in wild type mice and mice lacking mGlu2 or mGlu3. LY379268 induced similar LTD in wild type mice and mGlu3 knockout mice, whereas LTD was absent in mGlu2 knockout mice, indicating that mGlu2 activation is necessary for the induction of LTD in the SNr. These studies suggest a novel role for mGlu2 in the long-term regulation of excitatory transmission in the SNr and invite further exploration of mGlu2 as a therapeutic target for treating the motor symptoms of PD.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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19 MeSH Terms
The mGluR2 positive allosteric modulator BINA decreases cocaine self-administration and cue-induced cocaine-seeking and counteracts cocaine-induced enhancement of brain reward function in rats.
Jin X, Semenova S, Yang L, Ardecky R, Sheffler DJ, Dahl R, Conn PJ, Cosford ND, Markou A
(2010) Neuropsychopharmacology 35: 2021-36
MeSH Terms: Amino Acids, Analysis of Variance, Animals, Behavior, Animal, Biphenyl Compounds, Brain, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Transformed, Cocaine, Cues, Dopamine Uptake Inhibitors, Dose-Response Relationship, Drug, Drug Interactions, Excitatory Amino Acid Agonists, Extinction, Psychological, Feeding Behavior, Glutamic Acid, Humans, Indans, Male, Rats, Rats, Wistar, Receptors, Metabotropic Glutamate, Reinforcement Schedule, Reward, Self Administration, Time Factors
Show Abstract · Added February 19, 2015
Metabotropic glutamate receptor 2/3 (mGluR2/3) agonists were shown previously to nonselectively decrease both cocaine- and food-maintained responding in rats. mGluR2 positive allosteric modulators (PAMs) may represent improved therapeutic compounds because of their modulatory properties and higher selectivity for mGluR2. We analyzed the effects of the selective, brain penetrant, and systemically active mGluR2 PAM potassium 3'-([(2-cyclopentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl)biphenyl l-4-carboxylate (BINA) and the mGluR2/3 agonist LY379268 on intravenous cocaine self-administration and cocaine-seeking behavior in rats that had short (1 h, ShA) or long (6 h, LgA) access to cocaine. The effects of BINA on food responding and food-seeking behavior were also analyzed. Finally, we examined the effects of BINA on brain reward function and cocaine-induced reward enhancement using the intracranial self-stimulation procedure. BINA decreased cocaine self-administration in both ShA and LgA rats, with no effect on food self-administration. Alternatively, LY379268 nonselectively decreased both cocaine and food self-administration. BINA decreased cue-induced reinstatement of cocaine seeking with no effect on food seeking. The cocaine-induced enhancement of brain reward function was blocked by BINA, although the highest doses of BINA decreased brain reward function when administered alone, suggesting additive, rather than interactive, effects of BINA and cocaine. In conclusion, BINA attenuated the reinforcing and counteracted the reward-enhancing effects of cocaine and decreased cue-induced cocaine-seeking behavior, without affecting behaviors motivated by food reinforcement. The higher selectivity of BINA compared with an mGluR2/3 agonist for drug- vs food-motivated behaviors suggests a therapeutic role for mGluR2 PAMs for the treatment of cocaine addiction and possibly other drugs of abuse.
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27 MeSH Terms