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Results: 1 to 10 of 18

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Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience.
Sanghani NS, Haase VH
(2019) Adv Chronic Kidney Dis 26: 253-266
MeSH Terms: Anemia, Barbiturates, Glycine, Humans, Isoquinolines, Picolinic Acids, Prolyl-Hydroxylase Inhibitors, Renal Insufficiency, Chronic, Treatment Outcome
Show Abstract · Added March 24, 2020
Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral HIF-PHIs-daprodustat, roxadustat, and vadadustat-have now advanced to global phase III clinical development culminating in the recent licensing of roxadustat for oral anemia therapy in China. Here, we survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages, and deliberate over safety concerns regarding long-term administration in patients with renal anemia.
Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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1 Members
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9 MeSH Terms
Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.
Felts AS, Bollinger KA, Brassard CJ, Rodriguez AL, Morrison RD, Scott Daniels J, Blobaum AL, Niswender CM, Jones CK, Conn PJ, Emmitte KA, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 47-50
MeSH Terms: Allosteric Regulation, Animals, Dose-Response Relationship, Drug, Drug Discovery, Humans, Ligands, Molecular Structure, Picolinic Acids, Rats, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp character, uniform CYP-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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2 Members
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MeSH Terms
Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.
Haase VH, Chertow GM, Block GA, Pergola PE, deGoma EM, Khawaja Z, Sharma A, Maroni BJ, McCullough PA
(2019) Nephrol Dial Transplant 34: 90-99
MeSH Terms: Adolescent, Adult, Aged, Anemia, Erythropoiesis, Female, Glycine, Hematinics, Hemoglobins, Humans, Male, Middle Aged, Picolinic Acids, Prognosis, Renal Dialysis, Renal Insufficiency, Chronic, Young Adult
Show Abstract · Added April 22, 2018
Background - Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease.
Methods - In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7-8) and end-of-trial (Weeks 15-16) and was analyzed using available data (no imputation).
Results - Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations-analyzed using available data-remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat.
Conclusions - Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis.
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1 Members
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17 MeSH Terms
mGlu potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome.
Gogliotti RG, Senter RK, Fisher NM, Adams J, Zamorano R, Walker AG, Blobaum AL, Engers DW, Hopkins CR, Daniels JS, Jones CK, Lindsley CW, Xiang Z, Conn PJ, Niswender CM
(2017) Sci Transl Med 9:
MeSH Terms: Animals, Apnea, Autopsy, CA1 Region, Hippocampal, Cognition, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Humans, Long-Term Potentiation, Male, Memory, Methyl-CpG-Binding Protein 2, Mice, Motor Cortex, Neuronal Plasticity, Phenotype, Picolinic Acids, RNA, Messenger, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Respiration, Rett Syndrome, Social Behavior, Transcription, Genetic
Show Abstract · Added March 3, 2020
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the () gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)-CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in reduce mGlu protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu positive allosteric modulation decreases apneas in mice, suggesting that mGlu may be a potential therapeutic target for multiple aspects of the RTT phenotype.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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2 Members
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MeSH Terms
Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation.
Felts AS, Rodriguez AL, Blobaum AL, Morrison RD, Bates BS, Thompson Gray A, Rook JM, Tantawy MN, Byers FW, Chang S, Venable DF, Luscombe VB, Tamagnan GD, Niswender CM, Daniels JS, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2017) J Med Chem 60: 5072-5085
MeSH Terms: Allosteric Regulation, Aminopyridines, Animals, Chemistry Techniques, Synthetic, Drug Evaluation, Preclinical, HEK293 Cells, High-Throughput Screening Assays, Humans, Macaca fascicularis, Male, Mice, Inbred Strains, Picolinic Acids, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added March 21, 2018
Preclinical evidence in support of the potential utility of mGlu NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu versus the other mGlu receptors, and binding studies established a K value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.
0 Communities
4 Members
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16 MeSH Terms
HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism.
Haase VH
(2017) Hemodial Int 21 Suppl 1: S110-S124
MeSH Terms: Anemia, Barbiturates, Clinical Trials as Topic, Erythropoiesis, Erythropoietin, Glycine, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Iron, Isoquinolines, Picolinic Acids, Prolyl-Hydroxylase Inhibitors, Renal Dialysis
Show Abstract · Added April 28, 2017
A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.
© 2017 International Society for Hemodialysis.
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1 Members
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13 MeSH Terms
Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH
(2016) Kidney Int 90: 1115-1122
MeSH Terms: Aged, Anemia, Double-Blind Method, Female, Glycine, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Male, Middle Aged, Outcome Assessment, Health Care, Picolinic Acids, Renal Insufficiency, Chronic
Show Abstract · Added September 22, 2016
Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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1 Members
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12 MeSH Terms
Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4).
Gogliotti RD, Blobaum AL, Morrison RM, Daniels JS, Salovich JM, Cheung YY, Rodriguez AL, Loch MT, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR
(2016) Bioorg Med Chem Lett 26: 2984-2987
MeSH Terms: Allosteric Regulation, Animals, Microsomes, Liver, Picolinic Acids, Pyrroles, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Sulfonamides, Triazoles
Show Abstract · Added April 6, 2017
Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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2 Members
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10 MeSH Terms
Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).
Engers DW, Blobaum AL, Gogliotti RD, Cheung YY, Salovich JM, Garcia-Barrantes PM, Daniels JS, Morrison R, Jones CK, Soars MG, Zhuo X, Hurley J, Macor JE, Bronson JJ, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR
(2016) ACS Chem Neurosci 7: 1192-200
MeSH Terms: Allosteric Regulation, Amides, Animals, Chromatography, High Pressure Liquid, Excitatory Amino Acid Agents, Humans, Picolinic Acids, Pyrazoles, Pyridines, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu4) in preclinical rodent models of Parkinson's disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu4 PAM, N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo[4,3-b]pyridine head group. VU0418506 has been characterized as a potent and selective mGlu4 PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.
0 Communities
1 Members
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MeSH Terms
VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.
Nickols HH, Yuh JP, Gregory KJ, Morrison RD, Bates BS, Stauffer SR, Emmitte KA, Bubser M, Peng W, Nedelcovych MT, Thompson A, Lv X, Xiang Z, Daniels JS, Niswender CM, Lindsley CW, Jones CK, Conn PJ
(2016) J Pharmacol Exp Ther 356: 123-36
MeSH Terms: Allosteric Regulation, Animals, Anti-Anxiety Agents, Astrocytes, Behavior, Animal, Brain, Dose-Response Relationship, Drug, Drug Discovery, GABA Agonists, HEK293 Cells, Humans, Inositol Phosphates, MAP Kinase Signaling System, Membrane Potentials, Mice, Mice, Inbred C57BL, Picolinic Acids, Pyridines, Radioligand Assay, Rats, Receptor, Metabotropic Glutamate 5, Synaptic Transmission
Show Abstract · Added February 18, 2016
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [(3)H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
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22 MeSH Terms