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Impact of Acipimox Therapy on Free Fatty Acid Efflux and Endothelial Function in the Metabolic Syndrome: A Randomized Trial.
Aday AW, Goldfine AB, Gregory JM, Beckman JA
(2019) Obesity (Silver Spring) 27: 1812-1819
MeSH Terms: Adult, Aged, Blood Glucose, Cross-Over Studies, Double-Blind Method, Endothelium, Vascular, Fatty Acids, Nonesterified, Female, Humans, Hypolipidemic Agents, Insulin, Insulin Resistance, Lipid Metabolism, Male, Metabolic Syndrome, Middle Aged, Pyrazines, Vasodilation
Show Abstract · Added October 2, 2019
OBJECTIVE - Insulin resistance is associated with increased lipolysis and elevated concentrations of free fatty acids (FFA), which in turn contribute to impaired vascular function. It was hypothesized that lowering FFA with acipimox, a nicotinic acid derivative that impairs FFA efflux, would improve endothelial function, measured by flow-mediated dilation (FMD), in individuals with metabolic syndrome.
METHODS - A total of 18 participants with metabolic syndrome and 17 healthy controls were enrolled and treated with acipimox 250 mg orally every 6 hours or placebo for 7 days in a randomized, double-blind, crossover trial.
RESULTS - Acipimox reduced FFA concentrations among individuals with metabolic syndrome to near normal levels (P = 0.01), but there was no change among healthy controls (P = 0.17). Acipimox did not improve endothelial-dependent FMD in either group (metabolic syndrome: P = 0.42; healthy controls: P = 0.16), although endothelial-independent nitroglycerin-mediated dilation among those with metabolic syndrome tended to increase (20.3%, P = 0.06). There were no changes in blood lipids or markers of inflammation following therapy. There was minimal correlation between change in FMD and baseline measures of BMI ( ρ = -0.09) or waist circumference ( ρ = -0.15).
CONCLUSIONS - In groups with normal or elevated baseline FFA, short-term reductions do not improve endothelial function assessed by FMD.
© 2019 The Obesity Society.
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1 Members
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18 MeSH Terms
Discovery of a novel 3,4-dimethylcinnoline carboxamide M positive allosteric modulator (PAM) chemotype via scaffold hopping.
Temple KJ, Engers JL, Long MF, Gregro AR, Watson KJ, Chang S, Jenkins MT, Luscombe VB, Rodriguez AL, Niswender CM, Bridges TM, Conn PJ, Engers DW, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 126678
MeSH Terms: Allosteric Regulation, Amides, Azetidines, Benzene, Molecular Structure, Protein Binding, Pyrazines, Pyridines, Pyrimidines, Receptor, Muscarinic M4, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M PAM activity and improved clearance and protein binding profiles.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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1 Members
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11 MeSH Terms
Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels.
Kozek KA, Du Y, Sharma S, Prael FJ, Spitznagel BD, Kharade SV, Denton JS, Hopkins CR, Weaver CD
(2019) ACS Chem Neurosci 10: 358-370
MeSH Terms: Dose-Response Relationship, Drug, Drug Discovery, G Protein-Coupled Inwardly-Rectifying Potassium Channels, HEK293 Cells, Humans, Ion Channel Gating, Neurons, Pyrazines
Show Abstract · Added April 10, 2019
G protein-gated, inwardly rectifying, potassium (GIRK) channels are important regulators of cellular excitability throughout the body. GIRK channels are heterotetrameric and homotetrameric combinations of the K3.1-4 (GIRK1-4) subunits. Different subunit combinations are expressed throughout the central nervous system (CNS) and the periphery, and most of these combinations contain a GIRK1 subunit. For example, the predominance of GIRK channels in the CNS are composed of GIRK1 and GIRK2 subunits, while the GIRK channels in cardiac atrial myocytes are made up mostly of GIRK1 and GIRK4 subunits. Although the vast majority of GIRK channels contain a GIRK1 subunit, discrete populations of cells that express non-GIRK1-containing GIRK (non-GIRK1/X) channels do exist. For instance, dopaminergic neurons in the ventral tegmental area of the brain, associated with addiction and reward, do not express the GIRK1 subunit. Targeting these non-GIRK1/X channels with subunit-selective pharmacological probes could lead to important insights into how GIRK channels are involved in reward and addiction. Such insights may, in turn, reveal therapeutic opportunities for the treatment or prevention of addiction. Previously, our laboratory discovered small molecules that can specifically modulate the activity of GIRK1-containing GIRK channels. However, efforts to generate compounds active on non-GIRK1/X channels from these scaffolds have been unsuccessful. Recently, ivermectin was shown to modulate non-GIRK1/X channels, and historically, ivermectin is known to modulate a wide variety of neuronal channels and receptors. Further, ivermectin is a complex natural product, which makes it a challenging starting point for development of more selective, effective, and potent compounds. Thus, while ivermectin provides proof-of-concept as a non-GIRK1/X channel activator, it is of limited utility. Therefore, we sought to discover a synthetic small molecule that would serve as a starting point for the development of non-GIRK1/X channel modulators. To accomplish this, we used a high-throughput thallium flux assay to screen a 100 000-compound library in search of activators of homomeric GIRK2 channels. Using this approach, we discovered VU0529331, the first synthetic small molecule reported to activate non-GIRK1/X channels, to our knowledge. This discovery represents the first step toward developing potent and selective non-GIRK1/X channel probes. Such molecules will help elucidate the role of GIRK channels in addiction, potentially establishing a foundation for future development of therapies utilizing targeted GIRK channel modulation.
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8 MeSH Terms
Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia.
Conde-Ceide S, Alcázar J, Alonso de Diego SA, López S, Martín-Martín ML, Martínez-Viturro CM, Pena MA, Tong HM, Lavreysen H, Mackie C, Bridges TM, Daniels JS, Niswender CM, Jones CK, Macdonald GJ, Steckler T, Conn PJ, Stauffer SR, Lindsley CW, Bartolomé-Nebreda JM
(2016) Bioorg Med Chem Lett 26: 429-434
MeSH Terms: Allosteric Regulation, Animals, Antipsychotic Agents, HEK293 Cells, Humans, Male, Pyrazines, Pyrazoles, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Schizophrenia
Show Abstract · Added February 18, 2016
As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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3 Members
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11 MeSH Terms
A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments.
Mohni KN, Thompson PS, Luzwick JW, Glick GG, Pendleton CS, Lehmann BD, Pietenpol JA, Cortez D
(2015) PLoS One 10: e0125482
MeSH Terms: Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, Cell Survival, Cisplatin, DNA Repair, DNA-Directed DNA Polymerase, Drug Resistance, Neoplasm, Drug Synergism, Gene Library, HCT116 Cells, Humans, Intracellular Signaling Peptides and Proteins, Pyrazines, RNA, Small Interfering, Sulfones, Tumor Suppressor p53-Binding Protein 1
Show Abstract · Added February 4, 2016
The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic.
1 Communities
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18 MeSH Terms
Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression.
Jin R, Yamashita H, Yu X, Wang J, Franco OE, Wang Y, Hayward SW, Matusik RJ
(2015) Oncogene 34: 3700-10
MeSH Terms: Androgen Antagonists, Anilides, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Bortezomib, Cell Line, Tumor, Humans, Male, NF-kappa B, Nitriles, Prostatic Neoplasms, Castration-Resistant, Pyrazines, Receptors, Androgen, Signal Transduction, Tosyl Compounds, Xenograft Model Antitumor Assays
Show Abstract · Added January 20, 2015
Androgen receptor splicing variants (ARVs) that lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the new generation of high-affinity anti-androgens. However, the mechanism by which ARV expression is regulated is not fully understood. In this study, we show that the activation of classical nuclear factor-kappa B (NF-κB) signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen-sensitive PCa cells to become androgen-insensitive, whereas downregulation of NF-κB signaling inhibits ARV expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB-targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction of ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications as it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT).
1 Communities
3 Members
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17 MeSH Terms
Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm.
Devin JK, Pretorius M, Nian H, Yu C, Billings FT, Brown NJ
(2014) J Am Heart Assoc 3:
MeSH Terms: Adult, Cross-Over Studies, Dipeptidyl-Peptidase IV Inhibitors, Double-Blind Method, Female, Forearm, Glucagon-Like Peptide 1, Healthy Volunteers, Humans, Male, Middle Aged, Natriuretic Peptide, Brain, Pyrazines, Regional Blood Flow, Sitagliptin Phosphate, Triazoles, Vasodilation
Show Abstract · Added January 20, 2015
BACKGROUND - Dipeptidyl-peptidase 4 (DPP4) inhibitors improve glycemic control in patients with diabetes mellitus by preventing the degradation of glucagon-like peptide-1 (GLP-1). GLP-1 causes vasodilation in animal models but also increases sympathetic activity; the effect of GLP-1 in the human vasculature and how it is altered by DPP4 inhibition is not known. DPP4 also degrades the vasodilator brain natriuretic peptide (BNP) to a less potent metabolite. This study tested the hypothesis that DPP4 inhibition potentiates the vasodilator responses to GLP-1 and BNP in the human forearm.
METHOD AND RESULTS - Seventeen healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received DPP4 inhibitor (sitagliptin 200 mg by mouth) or placebo. Sitagliptin increased forearm blood flow and decreased forearm vascular resistance without affecting mean arterial pressure and pulse. GLP-1 and BNP were infused in incremental doses via brachial artery. Venous GLP-1 concentrations were significantly higher during sitagliptin use, yet there was no effect of GLP-1 on forearm blood flow in the presence or absence of sitagliptin. BNP caused dose-dependent vasodilation; however, sitagliptin did not affect this response. GLP-1 and BNP had no effect on net norepinephrine release.
CONCLUSIONS - These data suggest that GLP-1 does not act as a direct vasodilator in humans and does not contribute to sympathetic activation. Sitagliptin does not regulate vascular function in healthy humans by affecting the degradation of GLP-1 and BNP.
CLINICAL TRIAL REGISTRATION URL - www.clinicaltrials.gov/ Unique identifier: NCT01413542.
© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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17 MeSH Terms
Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.
Bates BS, Rodriguez AL, Felts AS, Morrison RD, Venable DF, Blobaum AL, Byers FW, Lawson KP, Daniels JS, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2014) Bioorg Med Chem Lett 24: 3307-14
MeSH Terms: Allosteric Site, Animals, Anxiety, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Discovery, Humans, Male, Mice, Molecular Structure, Picolinic Acids, Pyrazines, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship
Show Abstract · Added February 19, 2015
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and other anxiolytics, produced dose proportional effects.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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3 Members
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16 MeSH Terms
Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group.
Ciombor KK, Feng Y, Benson AB, Su Y, Horton L, Short SP, Kauh JS, Staley C, Mulcahy M, Powell M, Amiri KI, Richmond A, Berlin J
(2014) Invest New Drugs 32: 1017-27
MeSH Terms: Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Bortezomib, Carcinoma, Hepatocellular, Chemokine CCL5, Cytokines, Disease-Free Survival, Doxorubicin, Female, Humans, Liver Neoplasms, Male, Middle Aged, Pyrazines, Treatment Outcome, Vascular Endothelial Growth Factor A, Young Adult
Show Abstract · Added August 7, 2014
PURPOSE - To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival.
EXPERIMENTAL DESIGN - This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate.
RESULTS - Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment.
CONCLUSIONS - The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.
2 Communities
2 Members
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19 MeSH Terms
Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition.
Devin JK, Pretorius M, Nian H, Yu C, Billings FT, Brown NJ
(2014) Hypertension 63: 951-7
MeSH Terms: Adult, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Bradykinin, Cross-Over Studies, Dipeptidyl Peptidase 4, Double-Blind Method, Enalaprilat, Enzyme Inhibitors, Female, Heart Rate, Humans, Male, Middle Aged, Neurotransmitter Agents, Norepinephrine, Peptidyl-Dipeptidase A, Pyrazines, Sitagliptin Phosphate, Substance P, Sympathetic Nervous System, Triazoles, Vascular Resistance
Show Abstract · Added January 20, 2015
UNLABELLED - Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition.
CLINICAL TRIAL REGISTRATION - - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.
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23 MeSH Terms